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THE EFFICACY AND SAFETY OF AMLODIPINE
IN PEDIATRIC PATIENTS
John W. Rogan
A thesis submitted in conformity with the requirements for the
degree of Master of Science
Department of Pharmacology
University of Toronto
O Copyright by John W. Rogan 1997
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THE EFFICACY AND SAFETY OF AMLODIPINE
IN PEDIATRIC PATIENTS
Master of Science 1997
John W. Rogan
Department of Pharmacology, University of Toronto
ABSTRACT:
In order to determine the efficacy and safety of amlodipine in children three
clinical studies were conducted. The first study (retrospective) performed on 23
pediatric transplant and nephrology patients showed that an antihypertensive
regimen with amlodipine had both significantly lower systolic ( ~ ~ 0 . 0 5 ) and
diastolic (pc0.05) blood pressure than baseline therapy. A second retrospective
study on 15 pediatric bone marrow transplant patients confirmed the results of the
first study. A prospective study in eleven pediatric renal transplant patients
demonstrated that no significant difference existed between amlodipine and
nifedipine/felodipine in terms of mean 30-day blood pressure (systolic: p=0.09:
diastolic: p=0.27), mean day time blood pressure (systolic: p=0.78; diastolic:
p=0.65 ), mean nighttime blood pressure (systolic: p=0.96; diastolic: p=0.95), and
mean patient cornpliance (p=0.94). Arnlodipine was generally well tolerated in al1
three studies. Thus, amlodipine is safe and provides comparatively effective blood
pressure control in children. This dmg has unique clinical value in children due to
once-daily dosing as a liquid preparation.
1. 1 wish to thank Dr. Gideon Koren for his patience and guidance over the years.
Dr. Koren has no equals in the field of clinical pharmacology in terms of
knowledge and expertise.
2. 1 wish thank both Dr. Sohail Khattak and Dr. Doug Blowey for their help in
the set-up and completion of the three studies at the Hospital for Sick Children.
3. 1 would like to thank the rend transplant coordinators Rita Poole and Moira
Koms, the dialysis unit technician Mukesh Gajaria, Dr. Gerald Arbus. Dr.
Diane Hebert, Dr. Denis Geary. Dr. John Balfe, and al1 members of the
nephrology department at the Hospital for Sick Children. Their kindness
and help in recmiting patients and medical or technical advise was very
much appreciated.
4. Finally I would like to thank Pfizer Canada. Inc. Without their financial
support the studies conducted in this thesis would not have been possible.
Page
1 . INTRODUCTION ........................................................................................
........................................................................ Pediatric Hypertension
............................... Task Force on Blood Pressure Control in Children
.................. Second Task Force on Blood Pressure Control in Children
..................................................... Etiology of Childhood Hypertension
......... Drug-induced Causes of Post Transplantation Hypertension
............................................................ Adverse Effects of Cyclosporine
Incidence of Hypertension in Transplant Patients Following . . ................................................................. Cyclosporine Administration
Causes of Post-transplantation Hypertension in Renal
................................................................................. Transplant Patients
Long-term Health Concerns Associated With Post Transplantation
.......................................................................................... Hypertension
..... Pharmacological Treatment of Post Transplantation Hypertension
............................ Mechanisms of Cyclosporine-induced Hypertension
................................................................................. Calcium Channels 2+ ........................................................... Structure of L-type Ca Channel
Location of Calcium Channel Blocker Binding Sites in the
........................................................................................ Alphal subunit
............................ Mechanism of Action of Calcium Channel blockers
...................... First and Second Generation Calcium Channel Blockers
Arnlodipine .............................................................................................
Page
Chernistry ................................................................................................
........................................................................... Unique B inding Profile .
................................................................................ Vascular Selectivity
Long Duration of Action ........................................................................ . . B ioavailability ........................................................................................
Onset and Offset of Action ....................................................................
................................................. Adverse Effect Profile of Amlodipine
Benefits of Calcium Channel Blockers for the Treatment of
................................................... Post Transplantation Hypertension
................................................................................... Kidney Function
................................................................................... Natriuretic Effect
............................................................................... CelIular Protection
.............................................. Treatment of Pediatric Hypertension
.............. Potential Advantages of Amlodipine Treatrnent in Children
2 . PART 1: EFFICACY AND SAFETY OF AMLODIPINE IN
..... PEDIATRIC TRANSPLANT AND NEPHROLOGY PATIENTS . . ........................................................................ Hypothesis, Objectives
Methods ...............................................................................................
Results ..................................................................................................
3 . PART II: EFFICACY AND SAFETY OF AMLODIPINE IN
............ PEDIATRIC BONE MARRO W TRANSPLANT PATIENTS . . ......................................................................... Hypothesis, Objectives
................................................................................................. Methods
ResuIts ...................................................................................................
Page
4 . PART III: PROSPECTIVE STUDY OF THE EFFICACY
AND SAFETY OF AMLODIPINE IN PEDIATRIC RENAL
.................................................................... TRANSPLANT PATIENTS
Hypothesis. Objectives. Patients ........... .. .........................................
Inclusion Criteria, Exclusion Criteria, Methods ..................................
ResuIts ...................... ., .......................................................................
.......................................................................... ............ . 5 DISCUSSION ..
......................................................................................... . 6 CONCLUSION
......................................................................................... 7 . REFERENCES
...................................................................................... . 8 APPENDICES
LIST OF TABLES
Page
Table 1 . Characteristics of Pediatric Transplant and Nephrology
Patients .......................................................................................... 34
Table 2 . Blood Pressure (Mean IT SEM) ...................................................... 35
Table 3 . Semm Laboratory Values (Mean + SEM) .................. .... ......... 36
Table 4 . Characteristics of Pediatric Bone Marrow Transplant Patients .... 43
Table 5 . Mean Patient Blood Pressure and Z Scores Before and During . .
AmIodipine Therapy ...................................................................... 44
Table 6 . Characteristics of Pediatric Rend Transplant Patients ................. 55
Table 7 . Home 30-day Mean Blood Pressure ......................................... 56
LIST OF FIGURES
Page
............. Figure 1 : Subunit Components of the L-Type Calcium Channel ... 13
Figure 2: Structural Components of the Alpha, Subunit of the L-Type
.......................................... Calcium Channel ................. ......... 14
Figure 3: Common Chernical Structures of Dihydropyridine-Based
Calcium Channel Blockers .................... ..... ............................. 18
1. INTRODUCTION:
PEDIATRIC HYPERTENSION
The incidence of pediatric hypertension has been estimated at 1 to 3% in
children under 13 years of agel. Although its incidence in children is
significantly lower than in adults, hypertension is not rare in childhood and its
detection and subsequent control is a major concern in health care'.
Task Force on Blood Pressure Control in Children
Up until the late 1970s, very little data pertaining to pediatric
hypertension was available because no consensus existed on a proper definition
of hypertension in children and there was an absence of standardized
approaches in place for evaluation of this disease. In order to address these
issues. the Task Force on Blood Pressure Control in Children was created by
the National Heart. Lung, and Blood Institute in the United States in 1977.
A report was released by this task force in 1977 which consisted of sex-
and age-specific normalized blood pressure distribution curves in children
thathad been derived from blood pressure data collected from numerous
epidemiologic studies. In this report hypertension was defined as blood
pressure values above the 95th percentile for a given age and gender'13.
Second Task Force on Blood Pressure Control in Children
As more national data on blood pressure in children were collected in the
following decade. a second task force was created to re-examine the issue of
hypertension in this cohort. The task force's subsequent 1987 report compiled
normative blood pressure data on over 70,000 children and included minority
oroups for the first time (e.g. t fric an-~rnericans)? Percentiles specific for 2
age and sex were established and are currently considered the standard tool for
the interpretation of blood pressure in children'. Today. hypertension in a
~ i v e n child is defined as three accurate measurements taken on three separate 2
occasions that exceed the 95th percentile for age and sex4.
Since blood pressure increases with not only age. but also weight and
height during childhood, assessrnent of hypertension in childhood may be
complicated by the differential growth rate of children'. A reanalysis. of the
available blood pressure data by Rosner et al. used gender and ape as well as
height to classify blood pressure. The use of a child's height percentile
(derived from the standard growth curve) prevents the false conclusion that
very ta11 children are hypertensive when they are normotensive. and that very
short children have normal blood pressure when they are in fact hypertensive.
Thus. height age, rather than chronological age is thought by some researchers
to be a more superior determinate of blood pressure during adolescence, a
period when there are significant variations in growth '?
Etiologv of Childhood Hypertension
The underlying causes of hypertension differ substantially between the
pediatric and adult populations. For example, primary or essentid
hypertension accounts for over 90% of hypertension in adults but is rare in
early childhood. although its incidence increases with age in children7.!
In contrast, secondary causes of hypertension are responsible for
approxirnately 90% of hypertension in children under 10 years of age. The
majority of cases of secondary hypertension can be attributed to rend
parenchyrnal disease in children'. To a lesser extent. disorders of the
renovascular, cardiovascular. and endocrine systems as well as dmg-induced
1 0 - 1 3 causes have been implicated as underlying causes of pediatric hypertension .
The most difficult type of hypertension to treat is that associated with chronic
rend Mure ' .
DRUG-INDUCED CAUSES OF POST TRANSPLANTA'IION
HYPERTENSION
Two of the most cornrnonly used irnmunosuppressant agents,
cyclosporine and corticosteroids, are known to induce hypertension in
transplant patients'4. Cyclosporine was introduced in 1984 and was soon.
thereafter, widely used to treat many solid organ and bone marrow transplant
patients since it increased allograft survival without appearing to cause
suppression of the bone marrow and it did not increase the incidence of
15.16 opportunistic infections in treated individuals . For example, in the early
1980's a clinical trial demonstrated that the graft survival rate after rend
transplantation improved by approximately 1 0 8 following the introduction of
Adverse Effects of Cyclosporine
Unfortunately, nephrotoxicity and hypertension'* are major adverse
19.20 effects of cyclosporine administration in patients who have received rend ,
11 ??
bone marrow- .--, hepaticZ3, and cardiac2' transplants. For instance, Kone et
al.'5 demonstrated that 64% of bone marrow transplant patients studied (n=64)
developed acute renal failure following cyclosporine administration and the
incidence of systernic hypertension was approximately 75%. Both adverse
events typically developed within one month of the initiation of cyclosporine
therapy.
Incidence of Hypertension in Transplant Patients
Following Cvclosporine Administration
Various ~ tud ies '~ - )~ in adults have demonstrated that the incidence of
hypertension following renal transplantation increased from a range of 45%-
55% to one of 67%-86% following the use of cyclosporine. In contrast to
renal transplant patients, only a srnall percentage of adults (540%) who
received a bone marrow transplant were hypertensive prior to the routine use of
cyclosporine i 8.2 1.27.34-36 . One study found an incidence of hypertension in bone
marrow transplant patients (n=47) of approximately 5 0 6 following
cyclosporine therapy. This incidence of hypertension increased to 7 0 8 in
patients who also received corticoster~ids'~. Thus. it appears, for the rnost part,
that post transplantation hypertension in bone marrow transplant patients is
drug-induced. This is not always the case following r end transplantation.
Causes of Post Transplantation Hypertension
in RenaI Transplant Patients
Hypertension following renal transplantation is usually multifactorial in
nature and, as a result, is poorly understood since it is difficult to delineate the
contribution of different factors that are responsible for the disease in a given
patient. Both intrinsic and extrinsic causes of hypertension have been
identified.
Intrinsic causes of hypertension are usually those that result from direct
damage to the renal allograft and include acute and chronic rejection and the
recurrence of the original renal disease state (e.g., focal glomerulosclerosis)
which necessitated transplantation3'. Chronic rejection is the most common
cause of chronic post transplantation hypertension in renal transplant patients3'.
Post transplantation hypertension caused by renal artery stenosis. dmgs.
and the presence of a patient's native kidneys are extemal causes of this disease
since they do not directly damage the rend allograft. Native kidney-induced
hypertension is a specialized type of post-transplantation hypertension. Studies
have demonstrated that there was a greater prevalence of hypertension in
patients whose own kidneys were not removed pnor to transplantation
compared to those who had a nephrectomy before receiving their
transplants 37.30.40 . Further evidence showed hypertension improved or subsided
4 1.42 when the native kidneys were later removed following transplantation .
Hypertension induced by renal artery stenosis and native kidneys is comrnonly
corrected through surgical or radiological techniques.
Long-term Health Concerns Associated With
Post Transplantation Hvpertension
Hypertension following renal transplantation is considered a serious
long-term health issue that concems transplant physicians since this condition
43-45 is associated with a significant decrease in graft survival . Furthemore.
cardiovascular disorders remain the most significant cause of death in renal
transplant patients and hypertension is postulated to be the most important risk
-16.47 factor for cardiovascular rnorbidity and mortality in this population . For
instance, hypertension was found to be a major risk factor for atherosclerosis in
adult renal transplant
and rehabilitation".
patients and it has a negative effect on a patient's suwival
Physicians who treat children with rend transplants
should be concemed with the findings discussed above since pediatric patients
appear to have a greater incidence of post transplantation hypertension than
adul ts4'.
Pharmacological Treatment of Post Transplantation Hvpertension
The introduction of cyclosponne has changed the nature of post-
transplantation hypertension and has led to considerable changes in the
pharmacological treatrnent of this condition. Pnor to the introduction of
cyclosporine, the renin-angiotensin system appeared to play a major role in
most types of post-transplantation hypertension. but is thought now to play
only a minor roleL. Several clinical studies during the cyclosporine era have
suggested that the circulating renin-angiotensin systern is suppressed in
posttransplantation hypertension. even in the presence of sodium restriction5@
5 2 . In fact, the use of angiotensin-converting enzyme (ACE) inhibitors as
monotherapy for posttransplant hypertension has resulted in minimal
antihypertensive efficacy3? However, the combination of enalapril maleate
and a diuretic has been shown to be effective as treatment for post-
transplantation hypertension in hem transplant patients".
Since cyclosporine can induce hyperkalemia and acidosis by partially
inhibiting the rend secretion of potassium and hydrogen ions, ACE inhibitors
must be used with caution since they may aggravate hyperkalemia and
acidosis5'. Moreover. cyclosporine administration causes significant increases
in uric acid levels. so the use of diuretic therapy is often not encouraged to treat
transplant patients since this may worsen the hyperuricemia56.
Mechanisms of Cvclosporine-induced Hvpertension
The primary mechanism by which cyclosporine is believed to cause
acute nephrotoxicity is through vasoconstriction of the afferent arteriole of the
olomeru1i5'. This vasoconstrictive mechanism is also thought by many to 5
induce svstemic hypertension through decreased effective renal blood flow
(ERBF) which leads to a decrease in the glomerular filtration rate (GFR) and an
58.59 increase in intravascular volume via sodium retention .
However. cyclosporine is also thought by some investigators to cause
post transplantation hypertension through a primary mechanism involving
60.6 1 adrenergic-mediated vasoconstriction . It has been demonstrated in
experimental studies that renal nerves may play an important role in alterations
in both renal blood flow and sodium homeostasis following cyclosporine
administration. It was further shown that these effects were reversed or
prevented following denervation of the kidney or by adrenergic bl~ckade~'.~'.".
However, these results have been questioned since it was demonstrated
clinically that renal transplant patients who were functionally denervated still
exhibited cyclosporine-induced vasoconstriction and post-transplantation
hypertensionM.
Recent studies have demonstrated that calcium channel blockers can
partially reverse the vasoconstrictive effects of cyclosporine which makes
them an ideal class of antihypertensive dmgs for first-line treatment in
65-70 posttransplantation hypertension .
Before further discussing the benefits of using calcium channel blockers
for the treatment of cyclosporine-induced post-transplantation hypertension.
the properties of this class of antihypertensive will be discussed.
CALCIUM CHANNELS
Calcium channels are ion-seiective pores that are formed from
membrane- spanning proteins of cells in muscle and heart, which selectively
admit ca2' ions7'. Calcium channels are divided into two sub groups based on
their location and principal function: the calcium release channels of the
sarcoplasmic reticulum and the voltage-activated, transsarcolemmal channels.
The tïrst channel subtype allows ~ a " ions to move from storage loci in the
sarcoplasmic reticulum to the cytosol where these ions initiate contraction.
The latter channel subtype facilitates the voltage-dependent inward flux of
~ a " ions across a normally impermeable ce11 membrane7'.
The voltage-dependent calcium channels are present in most cells but are
not found in red blood cells or platelets73. This channel subtype is further
subdivided into L. T, N, and P-type voltage-activated ~ a " channels based on
their differing biophysical properties and sensitivity to specific chernicals and
toxins7'?
Al1 cornmercially available calcium channel blockers only affect the
function of L-type ca2+ channels although there is a novel type of
pharmaceutical agent (rnibefradil) being clinically tested that causes selective
blockade of the T-type (transient, low voltage) calcium ~hannel '~. L-type
calcium channels are unique in that they possess large ion conductance. remain
open for relatively long periods of time, and are inactivated at a relatively slow
rate. L-type channels are localized in skeletal. cardiac. and vascular muscle
and play a primary role in muscle contraction7'.
Structure of the L-type ~ a " Channel
The L-type channel is an oligomenc structure that is composed of
five subunits (ai,a2,R.y, and 6) and is assernbled in the sarcolemma with the al
77.78 subunit providing the channel's functional central pore (refer to figure 1,
page 13 ).
The al subunit (refer to figure 2, page 14 ) is comprised of 1873 amino
acids and consists of four repeating transmembrane motifs denoted 1, II. III,
and I V ~ ~ . Each motif is made up of six segments (denoted S ) and each segment
is connected to another by extracellular loops. Segments 2 and 3, and 4 and 5
of each motif and segments 6 and 1 of motifs 1 and II, of II and III, and III and
IV are connected to intracelliilar loops7'. The fourth segment (S4) of each of
the 4 repeating motifs (S4) is postulated to form a component of the voltage-
sensing mechanism of the ionophore, because it contains charged amino acid
residues at every third or fourth position77.
The a? and 6 subunits are two proteins linked by disulphide bonds and
are encoded by the same gene. The function of these subunits is not known
although it has been suggested that the 6 subunit acts as a membrane anchor for
the a? proteinxO. In addition, it has also been postulated that the a2/6 complex
may modulate the ability of the al-subunit to conduct ca2* ions and bind
calcium channel blockersx' .
The B-subunit has been clearly shown expenmentally to enhance the
ability of the al-subunit to conduct calcium ionsx'. The functional importance
of the y subunit has not been elucidated7'.
Location of Calcium Channel Blocker Binding Sites
--Subunit
The chernical structure of calcium channel blockers consists of those
which are dihydropyridine-based (e.g. nifedipine, felodipine, amlodipine) or
phenylalkylamine-based (e.g. verapamil) and those which are derived from
benzthiazepines (e.g. diltiazem). The binding of dihydropyridine-based
calcium channel blockers to the alphal-subunit differs prirnarily from that of
the other two classes of calcium channel blockers in that their binding sites are
located on the extracellular side of the ce11 membrane, as opposed to
intraceliularlyx3.
It is postulated that the dihydropyridine-based calcium channel blockers
may bind to three distinct high affinity binding site regions of the alpha,
subunit. These binding sites include amino acid residues located within
transmembrane segment 6 of both motifs III and IV and the extracellular loop
84-86 of segments 5 and 6 of motif III .
Mechanism of Action of Calcium Channel Blockers
Al1 three subclasses of calcium channel blockers have similar
mechanisms of action but have differ with respect to their pharmacokinetic
profile, adverse effects. and myocardial and vascular selectivity8'. Calcium
channel blockers inhibit the transmembrane influx of calcium ions into
vascular and cardiac muscle cells which results in vasodilation and a reduction
in peripheral vascular resistance?
First and Second Generation Calcium Channel Blockers
Calcium channel blockers are referred to as first or second generation
drugs. First-generation calcium channel blockers were the earliest form of
these type of antihypertensives developed for clinical use and include the
prototype compounds verapa.mil, diltiazem. and nifedipine. The second
aeneration calcium channel blockers were developed to overcome some of the 2
limitations inherent in their first-generation prototypes.
The limitations of the first-generation calcium channel blockers include
their:
1. relatively short duration of action
2. poor bioavailability when administered orally
3. lack of tissue selectivity
4. high frequency of unacceptable side-effects
5. wide variations in peak-to-trough plasma concentrations during the dosage
interval''
AMLODIPINE
Amlodipine is a relatively new, second-generation dihydropyridine-
based calcium channel-blocker. Other cornrnon examples of second generation
dihydropyndine calcium-channel blockers include felodipine. isradipine.
nicardipine. nimodipine. nisoldipine, and nitrendipine. The rationale for
synthesizing amlodipine was to create a dmg with a longer half-life and
improved bioavailability than its prototype, nifedipineW. However. it has
become more evident that amlodipine has many other advantates over both
first and second generation calcium channel blockers.
Chemistre
Amlodipine has unique physiochemical properties that set it apart from
al1 other dihydropyridine-based calcium channel blockers (figure 3, page 18).
The drug possesses a side chain in the 2-position of the dihydropyridine ring
which contains a terminal basic arnino group (pK, =8.6). As a result,
amlodipine is 948 ionized at physiological pH. This high degree of ionization
is one identifiable factor which may account for the water solubility of this
agent. Al1 other dihydropyridines in clinical use have pK, values below 3.0
and are neutral under these conditions. and are not water soluble".
FIELODIPINE AMLODIPINE
FIGURE 3: COMMON CHEMICAL STRUCTURES OF
DIHYDROPYFUDINE-BASED CALCIUM CHANNEL BLOCKERS
Unique Binding Profile
Amlodipine also binds to the a,-subunit of the calcium channel complex
in a unique manner since its specific binding c m be inhibited by not only
calcium channel blockers of the dihydropyridine class, but also by
phenylalkylamine-based and benzothiazepine-based calcium channel blockers.
It is postulated that amlodipine binds to the three major types of calcium
channel blocker binding sites but its primary site of action is located within the
Y ?-OS dihydropyridine binding domain of the calcium channel .
Vascular Selectvitv
Arnlodipine is more vascular selective than its prototype nifedipine and
other first-generation calcium channel blockers. The selectivity factor (relative
effect on the vasculature versus that on the myocardium) of amlodipine is gog6-
9 7 and it is 20'~ for nifedipine. In addition, the negative inotropic effect of
nifedipine is approximately five tirne that of amlodipineM. Calcium channel
blockers with less negative inotropy are preferred by physicians because there
is less chance of cardiac failure in patients, particularly in those with impaired
left ventricular function".
Long Duration of Action
Much of the long duration of arnlodipine results from its unique
pharmacokinetic profile. First, amlodipine possesses a longer duration of action
when cornpared to other calcium channel blockers, which permits once daily
dosing for 24-hour control of hypertension 100- 102 . The intrinsic plasma
elimination half-life of a single dose of amlodipine in adults is 36 hours, but
increases up to 45 hours following repeated dosing. Steady state plasma
concentrations of amlodipine are reached approxirnately 7 days after once-daily
repeated dosingH" . In contrast, short-acting nifedipine has an elimination half-
life of only 2 hours so that multiple daily dosing is requiredlWY.
Some factors responsible for the relatively long intrinsic elimination
half-life of amlodipine include its relatively slow rate of hepatic rnetaboli~m"'~
and unusually large volume of distribution (21 ~ k ~ ) ' ' ~ . One advantage of
possessing a long half-life is that it ensures there will be minimal fluctuations
in peak-to-trough plasma concentrations during a piven amlodipine dosage
interval. Amlodipine has a relatively low peak-to-trough plasma concentration
of 1.5,"' which is even substantially smaller than the values found in slow-
release formulations of other calcium channel blockers ( e g felodipine ER, 2.9;
nifedipine SR. L0.4) 107.108
BioavaiIabili tv
Because arnlodipine does not undergo extensive first-pass metabolisrn
and is completely absorbed from the gastrointestinal tract, it has the advantage
of possessing a relatively high bioavailability (80% in hypertensive a d ~ l t s ) ' ~ ' .
Many of the other calcium-channel blockers undego extensive first-pass
metabolism and. as a result, have low bioavailability percentages (e.g.
felodipine ER, 22%' 'O. nifedipine, 43%Im). Dmgs with a low bioavailability
(e-g. felodipine ER) tend to exhibit a high degree of inter- and intrapatient
variability in terrns of their pharmacokinetic profile and efficacy, and both
parameters can be profoundly altered by foodsl", fluids (e.g. grapefruit
juice' 'I a l~ohol"~) , and other dmgs (e.g. di;oxin' 14. cirnetidine' 15).
Onset and Offset of Action
When administered orally, amlodipine is absorbed completely and
relatively slowly with peak levels occuring at between 6 and 12 hours after
dosingIo3. The majority of the other second-generation dihydropyridine-based
calcium channel blockers take from 1 to 2 hours to reach peak plasma levels
after oral administration 116-120 with the exception of felodipine ER, which may
take up to 8 hours in some individualsitO. In addition to the slow rate of
absorption of amlodipine. the slow onset of action is also thought to result
from its relatively long hepatic transfer tirne"' and its slow rate of association
of this blocker to the calcium channel. Similarly, the relatively slow offset of
action is presurnably due to the slow rate of dissociation of arnlodipine from
92-94 the calcium channel .
Adverse Effect Profile of Amlodipine
Because calcium channel blockers act through a mechanism involving
vasodilation. the predominant adverse effects cornmonly associated with these
drugs are extensions of their pharmacological action and include peripheral
edema. headaches. facial flushing. and dizzinessf". Amlodipine has a low
incidence of these adverse effects and this is not surprising because they are
thought to result primarily from major fluctuations in peak- to-trough plasma
concentrations that are encountered more frequently in agents with a more
rapid onset and shorter duration of action than amlodipineU. In addition. it was
demonstrated that amlodipine has a lower incidence of withdrawals from
therapy due to adverse events than has nitrendipineF3. nifedipine retard
(PA)".', and felodipineP5 at doses that provide sirnilar reductions in blood
pressure. The results from these studies suggest that amlodipine is well
tolerated and may improve patient compliance.
BENEFITS OF CALCIUM CHANNEL BLOCKERS
FOR TEJE TREATMENT OF
POST TRANSPLANTATION HYPERTENSION
It has been mentioned earlier that calcium channel blockers may be
useful as first-line therapy of post transplantation hypertension. In a recent
double-blind crossover study, a significant reduction in blood pressure was
achieved with 10 mg amlodipine in hypertensive cyclospox-ine-treated adult
rend transplant patients126. Hypertension has been shown to cause renal
impairment and cause damage to the glomemli of the kidneyI2'. There is
increasing evidence that calcium channel blockers are useful as an
antihypertensive agent since they have beneficial effects on the kidney 128-131
Kidnev Function
The renoprotective effects of amlodipine and other calcium channel
blockers appear to result, in part, from a selective dilation of the preglomerular
blood vessels (i.e., afferent arteriole) that results in an increase in GFR under
experimental conditions when isolated perfused kidneys were preconstricted
with the potent vasoconstrictor angiotensin II 133.133
in a clinical setting, it was demonstrated that the GFR usually increased
while serurn creatinine levels dropped, when patients were treated with
arnlodipine ' 34. Another clinical study found that therapeutically relevant
amiodipine doses had no effect on filtration fraction even while renal vascular
resistance decreased by as much as ~ 5 % ' ) ~ .
Moreover, it has also been shown that effective renal blood flow is
unaltered following a significant reduction in the renal perfusion pressure by
arnlodipine and other calcium channel blockers 134.137 . Thus. there is strong
evidence that normal kidney function and renal blood flow is preserved during
arnlodipine treatment which makes it useful for treatment of hypertension
following transplantation and in patients with renal impairment ( e g , chronic
rend failure). Amlodipine can be safely administered to patients with differing
degrees of renal impairment since pharmacokinetic parameters such as
elimination half-life, area under the plasma concentration curve, and maximum
plasma concentrations are relatively unaffected'?
Natriure tic Effect
Calcium channel blockers, in contrast to other vasodilators, do not cause
sodium and water retention which would be counterproductive in the treatment
of hypertension. Amlodipine has been shown recently to have no effect on
either plasma or extracellular fluid volume"'. Specifically, it has been
established that amlodipine has a rnild but persistent natriuretic effect at the
level of the rend tubule through inhibition of tubular sodium reab~or~tion ' '~.
Cellular Protection
Amlodipine and other calcium channel blockers also provide protection
of the kidney through a direct protective effect at the cellular level by
decreasing the rate of mesangial ce11 proliferation. Such proliferation of this
ce11 type in the glomeruli is comrnon in many types of rend disease (e.g.
hypertension-induced glomemlar i n j ~ r ~ ) ' ~ * . Other cellular mechanisms
postulated and known to rnediate the renoprotective functions of calcium
channel blockers include a reduction of rend hypertrophy; a reduction in the
metabolic activity of the remnant kidney; an arnelioration of uremic
nephrocalcinosis; a postulated inhibition of pressure-induced calcium entry:
and decreased free radical production12'.
Furtherrnore, calcium channel blockers are also useful as
antihypertensive therapy in transplant patients since these dmgs have been
shown to ameliorate the nephrotoxic effects of cyclosporine ( e g , rend
ischemic tubular necrosis) that can lead to acute rend failure if untreated 341,142
in addition, it has documented that calcium channel blockers may potentiate
the efficacy of cyclosporine which presumably leads to improved graft
survivai "3.
TREATMENT OF PEDIATRIC HYPERTENSION
Most antihypertensive agents used in adults are also administered to
pediatric patients. Yet. there exists few data regarding the efficacy and long-
term safety in this cohort'. Calcium antagonists are in widespread use in
pediatric patients because of the lack of side effects at therapeutic doses2. In
the case of amlodipine, no studies have been published that examine the use of
this calcium channel blocker in the pediatric population.
Amlodipine has many advantages over other calcium channel blockers
that make it ideal for the once daily dosing in the treatment of hypertension. In
addition, there is evidence that amlodipine may be an ideal first-line agent for
the specific treatment of hypertension in patients who have undergone organ or
marrow transplantation or have an underlying rend disease.
Potential Advantages of Amlodipine Treatment in Children
Amlodipine also has other advantages which make it particularly
attractive to the pediatric population. First, amlodipine can be formulated as a
liquid preparation which is ideal for younger patients who are unable to
swallow the tablets of the other commercially available long-acting calcium
channel blockers. Furthemore, the comrnercially available dosage forms may
be too high for a given child's size. Al1 slow-release calcium channel blockers
depend on an intact delivery system for their long duration of action so that the
patient must swallow each tablet whole. As a liquid preparation, an arnlodipine
dose c m be fractionated so that more appropriate doses can be adrninistered ro
a child. Finally, arnlodipine may improve patient compliance since it is
administered once a day. One aspect of compliance to calcium channel blocker
therapy that may be improved in children treated with amlodipine is a potential
lower incidence of withdrawals of this drug due to unacceptable adverse
effects. Recall that there were fewer withdrawals of amlodipine thenpy in
adults due to adverse effects than other long-acting calcium channel blockers.
The purpose of this thesis was to examine the efficacy of amlodipine in
pediatric patients and to descibe the drug's short-term safety by two
experimental approaches. In the first part of the thesis the institutional
experience with amlodipine at the Hospital for Sick Children (Toronto.
Ontario) was examined by conducting a retrospective study in both transplant
patients and individuals with underlying rend abnormalities. The second part
of the thesis will again focus on this institutional experience with arnlodipine
but a more selective transplant cohort was examined. Finally, a prospective
study has been conducted involving pediatric rend transplant patients to
examine the efficacy, safety, and effect of this agent on patient compliance.
2. PART 1: EFFICACY AND SAFETY OF AMLODIPINE IN
PEDIATRIC TRANSPLANT AND NEPHROLOGY PATIENTS
HYPOTHESIS: The introduction of arnlodipine into an antihypertensive
regimen provides as effective blood pressure control as
baseline antihypertensive therapy in pediatric patients.
OBJECTIVES:
1.) To compare the efficacy of an antihypertensive
regimen that inciudes amlodipine to baseline
treatment for hypertension (Le. before the inclusion
of amlodipine).
2.) To compare common clinical laboratory results
before and after the introduction of amlodipine.
3.) To descnbe the short-term safety of amlodipine
in children.
M-ETHODS:
Pharmacy records at the Hospital for Sick Children were reviewed to
identify inpatients who had received amlodipine for treatment of hypertension
during the penod of July 1993-July 1995. The hospital charts of each patient
identified were reviewed and the following information was collected before
and during amlodipine therapy: age, weight. diagnosis most likely related to
the patient's hypertension; indications for amlodipine, temporally related
adverse events. systolic and diastolic blood pressure dunng hospitalization.
dosages of amlodipine and concomitant medications. and various clinical
laboratory parameters (serum creatinine, hemoglobin concentration, hematocrit
percentage, platelet and white blood ce11 counts, and serum K' and Na'
concentrations).
Amlodipine was administered to al1 patients in the second penod of
analysis. This agent either replaced one or more antihypertensive dmgs or was
added ont0 the patient's pre-existing antihypertensive regimen. The penod of
analysis pnor to the introduction of amlodipine was referred to as the baseline
treatment penod (Le. it includes a patient's antihypertensive regimen in the
absence of amlodipine). The doses of each antihypertensive agent in the
baseline treatment period were raised in a stepwise rnanner to clinically
acceptable maximum levels in order to control each child's blood pressure. If
such blood pressure control was not achieved. amlodipine therapy was then
introduced. In most children in this study, adodipine was introduced for
reasons of convenience and not because of poor blood pressure control. The
blood pressure data before and dunng amlodipine therapy corresponds to the
maximum dose(s) of antihypertensive agents used.
The blood pressure was measured by nurses on the various hospital
wards using a Dinamap monitor (Critikon, Inc.) with a Dura cuff (Medicare,
Inc.) for most patients. However. Hewlett Packard electrocardigram units with
calibrated V-Lok cuffs (W.A. Baum Co.) were also used in the cardiac
transplant patients to observe their cardiac function. Typically. blood pressure
measurements were recorded six times per day (Le. every 4 hours), but this
number varied from three to fifteen depending on the status of the child's blood
pressure on a given day. Manual blood pressure readings were occassionally
taken with a Tycos sphygmomanometer to confirm the accuracy of a given
measurernent.
The "overall" mean systolic (SBP) and diastolic blood pressure (DBP)
measurements of each patient were calculated in both periods of analysis (Le.,
before and following the introduction of amlodipine). The "overall" mean
blood pressure was defined as the average of the mean daily blood pressure
readings calculated for each patient in both penods of analysis. The "overall"
means (SBP and DBP) of each patient for the analysis periods before and
following amlodipine treatment were compared using Student's paired t-tests.
Patients were included in this retrospective snidy if at least 3 days of blood
pressure data were available for each period of analysis (i.e. before and during
the commencement of amlodipine therapy). Comparisons of the means of each
individual clinical laboratory parameter prior to and during amlodipine
administration were also conducted. Statistical cornparisons were performed
using a Student's paired t-test (SigmastatB). The data is presented as mean I
SEM.
RESULTS:
Pediatric Transplant and Nephroloey Patient Characteristics (Table 1):
Twenty-three of the twenty-eight patients identified through the use of
pharmacy records had sufficient blood pressure data to be included in this
study but two of the younger patients did not have any recorded diastolic blood
pressure readings. The general characteristics of each patient are listed in
Table 1. The median age of the cohort was 7 years ( range: 2 weeks to 17
years) and included 16 males. The underlying diseases of the cohort were
heterogeneous in nature but involved a large number of patients with
underlying rend abnormalities. Almost half of the patients had received an
organ or bone marrow transplant. Al1 patients were receiving antihypertensive
therapy prior to the introduction of amlodipine. The dose of this calcium
channel blocker was adrninistered orally, once-a-day in al1 23 patients.
Amlodipine was used as replacement for other calcium channel blockers (eg.
nifedipine) in 19 individuals. The mean initial amlodipine dose used to
inititiate therapy was 0.14 f 0.01 mg/kg/day (range: 0.05 to 0.24). An increase
in amlodipine dose was required in ten (43%) patients which resulted in a mean
maximal dose of 0.22 f 0.03 mg/kg/day (range: 0.08 to 0.66). A Student's
paired t-test demonstrated that a significant difference existed between the
mean initial and maximum amlodipine dosage (p = 0.0 1).
Blood Pressure (Table II):
Using Student's paired t-test, the mean SBP and DBP were significantly
lower following the introduction of amlodipine as compared to baseline
antihypertensive therapy (2.5 I 1.1 mm Hg and 3.1 f 1.5 mm Hg, respectively;
p < 0.05). Following the introduction of amlodipine, fifteen out of 23 (65%)
patients each experienced a mean decrease in SBP while 13 out of 21 patients
(7 1%) had a mean reduction in DBP.
Laboratorv Data (Table III):
There were no significant changes in mean hematocrït percentage, mean
semm concentrations of creatinine, potassium, sodium, and hemoglobin, nor in
mean platelet and Ieukocyte counts following the initiation of arnlodipine
therapy. However. there was a clinically nonsignificant upward trend in serum
potassium and downward trend in the leukocyte count.
Adverse Dmp Reactions:
There were no adverse drug reactions ternporally associated with
amlodipine therapy in the majority of patients. However. one patient
developed a urticarid rash during amlodipine treatment which subsided despite
the continuation of this calcium channel blocker.
Table 1: Characteristics of Pediatric Nephrologv and Tramp tant Patients
Patient Age Gender Diagnosis
Number (Yrç)
An tihypertensives Arnlodipine
Prior to Amiodipine Dose( mg/kg/d)
InitialmIax
Chronic Rend Failurc
AHUS
Rend Transplant
BPD
Chronic Renal Failure
Bone Marrow
Transplant
Hrmt Transplant
ECMO
Hcart Transplm t
Chronic Rcnal Failure
Rend Transplant
Rcnal Transplant
Bone Marrow
Transplant
Rcnal Xrtery S tcnosis
Rcnal Transplant
Chronic Renal Failure
Hcart Transplant
Rend Transplant
Glornenilonephritis
Rcnal Transplant
Chronic Renal Failure
Rcnal Transplant
Chronic Renal Failurc
Furosemide
Felodipine*
Nif-PA*. Nadolol*
Hydralsizine*. HCTZ
Ni t-SA*. Capropril*
LabctoloI*
Nif-SA*. Furosernide
Nif-SA*
Nif-SA*
Nif-SA*. Captopril*
Nif-XL*
Nif-SA*
Nif-PA*
Nif-PA*. Nadolol. HCTZ
Nif-XL*
Nif-SA*
Enrilapri 1 *. Furosernide
Nif-XL*
Nif-PA*
Ni f-PAF
Nif-XL*. Hydralazine
Nif-PA*
Nif-PA*. Hydralrizinc
* discontinued with amlodipine therapy; Nif, nifedipine: SA. short-acting; PA. prolonged action; XL. extended release: HCTZ. hydrochlorothiazide: ECMO. extracorporeal membrane oxygenation: BPD. bronchopulmonary dysplasia: AHUS. atypical hemolytic uremic syndrome
Table II: Blood Pressure (Mean f SEM)
Before Amlodipine During
Amlodipine
p-value
Systolic Blood
Pressure
(n=23)
Diastolic Blood
Pressure
(n=21)
*: ** p-value was based on a Student's paired t-test in both cases
Before Arnlodipine During p-value
Amlodi pine
(n= 18)
(n=18)
Sodium (rnrnoUL) 137 I 0.8 137 I 0.6 0.79
Potassium
(mmoVL)
Platelets ( 1 0 ' ~ )
Hemoglobin (g/L) 109 + 4.1
Hematocrit ( % ) 33 -t 1.3 32 -t. 1.2 0.38
3. PART II: EFFICACY AND SAFETY OF AMLODIPINE IN
PEDIATRIC BONE MARROW TRANSPLANT PATIENTS
A second retrospective study was conducted on a more selective
pediatric cohort to determine if the positive results with regards to the eficacy
of amlodipine in the first retrospective study were reproducible. The cohort
examined here was more homogeneous than the first since al1 patients had
undergone a similar medical procedure (Le. bone marrow transplantation) and
presumably were subject to more sirnilar phamacological strategies to treat
their hypertension since it developed following the use of cyclosporine and
corticosteroids.
HYPOTHESIS: The incorporation of amlodipine into an antihypertensive
regimen provides blood pressure control similar to that of
baseline therapy in pediatric bone marrow transplant
patients.
OBJECTIVES:
1.) To compare the efficacy of an antihypertensive
regimen that includes amlodipine to baseline
therapy before the introduction of this calcium
channel blocker.
2.) To describe the short-term safety of amlodipine.
nmTHODS:
Thirteen pediatric bone rnarrow transplant inpatients who had received
amlodipine treatment at the Hospital for Sick Children were identified using
pharmacy records. The patients' charts were then reviewed and the period of
analysis of antihypertensive therapy ranged from May 1994 to June 1996 and
encompassed periods before and during amlodipine treatment. The following
information was extracted for each patient: age; weight; condition responsible
for bone marrow transplantation; indications for the use of amlodipine: systolic
blood pressure (SBP) and diastolic blood pressure (DBP) measurements, and
adverse events recorded during amlodipine treatment. The results of two bone
marrow transplant patients reviewed in the first retrospective study (refer to
Table 1) were pooled with the remaining 13 patients to bnng the cohort sample
size of this study to 15. The standard techniques and equipment used by the
nurses to measure blood pressure data are the same as those listed in the
methods section of the first retrospective study (page 30 ).
As in the first retrospective study, the mean SBP and DBP measurements
of each patient were used for comparison of the efficacy of the two treatment
periods: before and during arnlodipine therapy. However, in contrast to the
initial retrospective study, the period of analysis before amlodipine was
standardized for each patient to the three days immediately prior to its
introduction since this was likely the tirneframe when the patient may have
been hypertensive and the physician was contemplating whether to substitute
arnlodipine for another blood pressure-reducing agent or to incorporate it into
the antihypertensive regimen.
Furthemore, the arnlodipine treatrnent analysis period in this second
study was set to begin from the fifth day following the commencement of
amlodipine therapy since. in children, it should theoretically take about one
week for steady state levels of amlodipine to be reached in the plasma resulting
in clinically relevant reductions in blood pressure. The fifth day into
arnlodipine treatment (as opposed to the seventh day) was chosen as a starting
point in order to allow for a minimum of at least 3 days of blood pressure data
for each of our patients. It is a reasonable trade-off since amlodipine levels at
the fifth day should be fairly close to steady state levels. The blood pressure
data are presented as cohort mean + SEM. Individual mean blood pressure
measurements are also displayed in each analysis penod for each child.
Statistical cornparisons of SBP and DBP were conducted using Student's
paired t-tests (SigmastatB).
RESULTS:
Characteristics of Pediatric Bone Marrow Transplant Patients (Table IV):
The median age of the patient cohort examined in this study was eight
years (range: 1 to 17 years); nine children were female. Amlodipine was
administered as an oral once daily dose to al1 patients. The mean initial dose of
arnlodipine used for the treatment of hypertension was 0.12 I 0.0 1 rng/kg/day.
Four patients required an increase in arnlodipine dosage, which resulted in a
mean maximum dose of 0.16 k 0.02 mg/kg/day. Patient # 13 was given a
loading dose of 10 mg on the first day of treatment and received maintenance
doses of 5 mg per day thereafter. A Student's paired t-test dernonstrated that a
significant difference existed between mean initial and maximal amlodipine
dosage (p = 0.03).
Antihypertensive Regimen Pnor to and Dunng Amlodipine:
In six patients. amlodipine was the sole antihypertensive dmg used.
while in the remaining cases the drug was used in combination with other
blood pressure-lowering dmgs. Amlodipine replaced a single calcium channel
blocker in six cases whereas in another child it was substituted for two calcium
channel blockers. Amlodipine also replaced a diuretic in one case and an ACE
inhibitor in another. Furthemore, this drug replaced both a calcium channel
blocker and diuretic in one individual and replaced a P-blocker and calcium
channel blocker in another child. Moreover, amlodipine was also introduced in
one patient to replace both a vasodilator and diuretic. while in another child it
was administered in combination with an ACE inhibitor to replace two calcium
channel blockers and a vasodilator. Finally, in two cases this calcium channel
blocker was added to each patient's antihypertensive regimen.
Blood Pressure (Table V):
Eleven of the fifteen patients (73%) had an overall individual reduction
in both systolic and diastolic blood pressure following the introduction of
amlodipine (maximum dose) for the treatment of post-transplantation
hypertension. Using Student's paired t-test, both the mean SBP and DBP were
significantly lower in this patient cohort during amlodipine therapy than before
its use (6.5 + 2.7 mm Hg and 5.9 + 2.7 mm Hg, respectively; p < 0.05). Note in
table V that z scores are also given for each patient's mean blood pressure
(SBP and DBP) before and during arnlodipine therapy. The z score indicates
the relative percentage by which each patient's mean blood pressure exceeds
(positive values) the 95th blood pressure percentile for hisher age and gender.
A Negative z score indicates the relative percentage in which a patient's mean
blood pressure appears below hisher corresponding 95th percentile for biood
pressure.
Adverse Druo Events:
Two patients experienced ankle edema dunng arnlodipine therapy that
failed to respond to diuretic therapy (novospirozone). This adverse event led to
the discontinuation of amiodipine treatment in both individuais (patients 1 and
3). The ankle edema subsided in both chiidren approximately 2 to 3 days after
the cessation of arnlodipine therapy.
Table IV: Characteristics of Pediatric Bone Marrow Transplant Patients
Patient ~ e n h e r Age Weight Diagnasis Amlodipine Dose
Nurnber (Yrs) (kg) (rn@R/day)
Ini tial\h.laximum
7 -
i
4
5
6
7
8
9
I O
I I
12
13
I - i
15
Sevrre Combined Irnmunodet'ficiençy
Acutc Lymphobtmic Lcukemiri
Chcdiak-Higashi Syndrome
Scvcre Cornbined Imrnunodclïciency
Hurler's Syndromc
Neuroblastoma
Fanconi's Xnemiri
Aplastic Ancrniri
Aplristic Xncmiri
Chronic XlycIo_eenous Leukcrniri
Schwxhmrin-Diamonci Syndromc
Aplristic Ancmiri
Acutr: ,Myclogcnous Lcukrmiri
Acute Lymphoblristic Lrukemiri
Acurc Lymphoblastic
Patient Num ber
1
3 -
3
4
5
6
7
8
9
IO
1 1
12
13
14
15
Mean
Table V: Mean Blood Pressure and Z Scores
Before and During Amlodipine Therapv
Pre-amlodipine SBP
(mmHg) [%1 132.5 lll.41
Post-amlodipine SBP
(mmHg) I%l 1 15.3 [4.7]
Pm-amIodi pine DBP
(mmHg) [%1 77.5 [4.7]
Post-amlodipine DBP
(mm Hg) [%l 77.3 [4.5]
* p-value c 0.05 (Student's paired t-test) ** p-value < O.OS(Student's paired t-test) SBP, systolic blood pressure; DBP, diastolic blood pressures Note: numeric values in parentheses represent z score of mean blood pressures relative to the 95th percentile for each patient's age and gender.
4. PART III: PROSPECTIVE STUDY OF THE EFFICACY
OF AMLODIPINE IN PEDIATRIC RENAL TRANSPLANT
PATIENTS
HYPOTHESIS: Amlodipine controls blood pressure in hypertensive
pediatric rend transplant patients as effectively as
nifedipine or felodipine.
OBJECTIVES:
1 ) To investigate the efficacy of amlodipine in controlling
elevated blood pressure as compared to nifedipine or
felodipine.
2) To compare the patient's cornpliance between
arnlodipine and nifedipine/felodipine.
3) To describe the safety of amlodipine. nifedipine. and
felodipine.
PATIENTS:
Eleven patients between the ages of 3 and 18 years were recruited
from the nephrology outpatient clinic at the Hospital for Sick Children.
INCLUSION CRITERIA:
Witten and verbal inforrned consent.
Patient was receiving either nifedipine or felodipine for treatment
of hypertension pnor to his/her participation in this study.
Patient had stable blood pressure control as defined as no change
in antihypertensive medications or dosages during the month
prior to recruitment.
Patient had received a rend transplant at least 3 months prior
to recruitment.
EXCLUSION CRITElUA:
1 .) Known allergy to amlodipine, nifedipine. or felodipine.
METHODS:
The study comprised two treatment phases: arnlodipine and nifedipine
(or felodipine). No patients had never received amlodipine for treatrnent of
hypertension. In a randomized. cross-over design each subject received
amlodipine and nifedipine (or felodipine) in separate 30 day treatment periods.
Using a random table. the first treatment period (arnlodipine or
nifedipinelfelodipine) was randomized before the start of the study. Thus, some
would receive amlodipine therapy first while other patients would start the
study with nifedipine or felodipine. There was no washout period between
each treatment phase and the patients and investigator were unblinded as to
which medication was being administered.
Dosing Procedure:
Amlodipine:
Amlodipine (NorvascTM. ffizer) is commercially available in 7.5. 5
(scored), and 10 mg tablets. Patients in the nephrology clinic at our institution
are typically adrninistered an initial arnlodipine dose of 0.10 mgkg once a day.
.An exact initial dose to match a patient's body weight can be achieved by
dissolving an amlodipine tablet in water
standard procedure involves dissolving
using a dissolvant dose container. The
a 5 mg tablet in 5 mL of water. The
appropriate dose (volume) is then obtained from the dissolved solution (each
mL contains 1 mg) using a syringe and the remainder of the solution is
discarded. The practice of obtaining a smaller dose is necessary for very young
patients (e-g. newborns) who cannot swallow the amlodipine tablets or who
require a dose smaller than one tablet to match their body weight. Since al1 of
the patients recruited in this study were older and did not fit the
aforementioned criteria (i.e.. unable to swallow arnlodipine tablets, tablet dose
inappropriate for size), each was administered a single intact tablet dose which
was approximately 0.1 mgkg.
Patients received either an initial single daily 2.5 mg tablet or a
maximum initial single daily 5mg tablet. If the patient's blood pressure was
not in the normotensive range (< 95th percentile for age) after approximately 5
to 7 days of amlodipine therapy. the staff nephrologist was informed by the
patient's parent and it was decided whether to raise the arnlodipine dose by 50
to 100%. The maximum daily dose permitted by this study was 10 mg. The
primary investigator was blinded to any dose changes ordered by the staff
nephrologist.
Nifedipine or Felodipine:
Since each patient recruited was receiving either nifedipine or felodipine
prior to his/her participation in the study, no dose changes were necessary for
either calcium channel blocker during the study. The appropriate daily doses
had been previously determined by the staff nephrologist so as to obtain blood
pressure measurements in the normotensive range (c 95th percentile for age).
Blood Pressure Monitoring:
Blood pressure was monitored at home manually with either a mercury
sphygmomanometer or an automated oscillometric device (Critikon Inc.,
Tampa Ha.). The adult caregiver (parent) of each patient was instructed to take
blood pressure measurements twice daily (one measurement in the morning and
another in the evening at approxirnately the same times). Each parent had been
properly trained by a nurse to measure the child's blood pressure using a
standardized technique with the patient in the supine position4. To measure
blood pressure accurately, it is critical to use the appropriate cuff size. For
example, the use of a cuff that is too small will give false high blood pressure
readinss 144,145 . The cuff must be wide enough so that the bladder completely
encircles the circurnference of the patient's a m and wide enough to cover
approximately three quarters of the upper arm between the olecranon and the
top of the shoulder. There must be sufficient roorn at the antecubital fossa to
place the stethoscope there comfortably if a mercury sphygmomanometer is
used. The cuff should not be placed too high around the upper arm so as to
obstmct the patient's axilla'.
During the final 2 weeks of each treatment phase, ambulatory blood
pressure monitoring was also performed over a 24-hour interval using either a
Takeda blood pressure monitor model TM 2420 (A & D Engineering Inc.,
California) or an ambulatory blood pressure monitor model 90207 (Spacelabs
Medical. Mississauga, ON). Each monitor was preset to measure the blood
pressure every 30 minutes, from 9 A.M. to 10 P.M., and every 60 minutes from
10 P.M. to 9 A.M. The patient's heart rate was also recorded during these two
intervals. For the majority of patients, the blood pressure monitors were
properly placed on the patient directly by the trained investigator. However,
patients who lived outside of Metropolitan Toronto were given a
demonstration of the proper set-up while attending the nephrology outpatient
clinic at the Hospital for Sick Children. At the appropriate time, the monitors
were later shipped at the appropriate tirne to each patient's residence. with an
instructional video detailing the standard set-up of the monitoring equiprnent.
Each patient was supplied with a 24 hour diary to record his/her activities
throughout the monitoring period.
In order to ensure consistent blood pressure readings were obtained
during ambulatory blood pressure monitoring. the patient was instructed to
remain still during each measurement. Blood pressure measurements are also
influenced by the arm position. There is an approximate increase of 10 to 12
mm Hg in both systolic and diastolic blood pressure as the arm is lowered from
the outstreched position perpendicular to the trunk to a a m position parallel to
the tmnkl"f As a result, each patient was instructed to place the arm parallel
to the trunk for each blood pressure measurement. Furthermore, patients were
also instructed not to talk during a blood pressure measurement since this is a
potent pressor stimulus. For example, reading aloud has been shown to cause
an immediate increase in blood pressure of about 10/7 mm Hg in normotensive
subjects which subsides immediately after the individuals stop reading 147.148
In both the twice-daily manual and 24 hour blood pressure measuring
techniques the cuff was placed on the left upper arm of the patient.
Adverse Events:
Each patient was instructed to record any adverse events experienced
each day throughout the study.
Compliance:
Compliance was assessed using the Medication Event Monitoring
System (MEMS. Aprex. California). The MEMSB TrackCapTM is a medication
bottle cap that contains a microelectronic tracking device. This electronic chip
in the iid of the cap records the date and time when a medication bottle
containing a study dmg was opened. The parents and children were not aware
of the purpose of this electronic monitoring device.
Statistics:
With mean diastolic blood pressure as a primary endpoint. a sample of
eleven patients will be sufficient to show a median effect size difference in
blood pressure between the two drugs with an alpha of 0.05 and a power of
channel blockers class and the dosages of these drugs were identical in each
treatment phase of the study.
Blood Pressure Control:
1. Home 30-Day Mean Blood Pressure (Table VII):
Using Student's paired t-tests there was not a significant difference in
both the cohort's mean 30-day systolic blood pressure and mean 30-day
diastolic blood pressure when comparing the two treatment phases (arnlodipine
and nifedipine/felodipine). Eight patients had a reduction in their individual
mean SBP with amlodipine therapy, whereas six patients experienced a lower
mean DBP during this treatment phase.
2. Twenty-four Hour Blood Pressure:
Nine of the eleven patients completed 24-hour blood pressure
monitoring for both drug treatment periods.
A) Day time Blood Pressure :
Using Student's paired t-tests. there was no statistical difference in mean
daytime (9 A.M.-IO P.M.) systolic blood pressure (amlodipine: 126.6 13.4 mm
Hg; nifedipine/felodipine: 127.5 + 3.4 mm Hg; p = 0.78). In addition, there
was no statistical difference in mean daytime diastolic blood pressure
(amlodipine: 78.6 f 2.2 mm Hg; nifedipine/felodipine: 77.5 I 2.2 mm Hg; p =
0.65).
B) Nighttime Blood Pressure:
No statistical mean difference was found between each treatrnent penod
for the patients in nighttime systolic blood pressure (amlodipine: 119.5 f 2.9
mm Hg; nifedipinelfelodipine: 119.3 + 3.3 mm Hg; p = 0.96). Furthemore. no
statistical mean difference was observed in the nighttime diastolic blood
pressure (arnlodipine: 74.7 I 3.2 mm Hg; nifedipine/felodipine: 74.5 + 3.1
mm Hg; p = 0.95).
Adverse Events:
No adverse events were reported by the patients during the two calcium
channel blocker treatment periods.
Cornpliance:
There was no significant difference between the two calcium channel
blocker treatment periods in mean patient compliance (Le. percentage of drug
taken versus prescribed amount) during each 30-day assessrnent period
between the two calcium channel blocker treatment penods (adodipine: 93.4
L- 1.7 %; nifedipinelfelodipine: 93.4 + 1.6 8; p = 0.94. Student's paired t-test).
Patient Age Geader Weight Rend Amlodipine ~ a " Channel Number (Y rs) (kg) Diagnosis Dosage Blocker
( mg/kg/day Therapy Ini tial\Ma.x Prior to
Amlodipine
1 9 F 3 5 Focal Segmental 0.07\0.07 Nifedipinc PA G IomcruIosclerosis 20 mg o.d.
Autosornd Dominant 7 - 1 O LM 27 Poiycystic Kidncy O. 1 O\O. 1 O Ni fedipine XL
Diserise 30 mg 0.d.
7 12 M 30 Rend Dy splasia 0.08\0.08 Nifcdipine XL 30 mg O-d.
4 14 M 3 7 Cystinosis 0.07\0.07 Fclodipine E.R 15 mg o.d
5 16 IM 45 Cystinosis O. 1 1\0.11 Fclodipinc E.R. 10 mg o.d.
h 16 F 46 Radiation-induced O. 1 1\02? Nifedipinc XL Nephntis 30 mg b.i.d.
7 16 M 7 2 Alport's Syndrome O.On0. 1 O Nifcdipinc XL 30 mg b.i.d.
X Ih F 90 Unknown 0.06\0.1 1 Nifcdipinc XL 60 mg o-d.
9 17 F 3 4 Bilateral Wilrn' s Tumour O. 1 5W.22 Ftdodipinc ER I O mg b.1.d.
10 17 F 3 5 Adult Polycystic 0. 1 4\0. i 4 Nifedipinc XL Kidncy Discrisc 30 mg 0.d.
I I 17 M 60 Ncphrotic Sy ndromc 0.08\0.08 Nifcdipinc XL
Table VII: Home 30-day Mean Blood Pressure
Patient S.B.P. During S.B.P. During D.B.P. During D.B.P. During
Number Nifedipine/Felodipine Amlodipine Nifedipine/Felodipine Amlodipine
(mm Hg) (mm Hg) (mm Hg) (mm Hg)
- - - - -
* p-value = 0.09 (Student's paired t-test)
** p-value = 0.37 (Student's paired t-test)
5. DISCUSSION:
ve sti dies demon
Part 1 and Part II:
Both retrospecti strated a statistically significant
reduction of both systolic and diastolic blood pressure in children receiving
phmacological treatment for hypertension when amlodipine replaced one or
more antihypertensive dmgs or was added ont0 an existing antihypertensive
regimen. The majority of pediatric patients in both studies experienced
improved blood pressure control dunng the administration of arnlodipine. In
certain individual patients (e.;., numbers 12 and 14 in the second retrospective
study; table V) the reduction in blood pressure was clinically significant since
it moved their blood pressure substantially below the 95th percentile so that
these children were no longer considered to be hypertensive. However, in other
individuals the change in mean blood pressure was marginal (e.g. patients 2
and 3, table V).
Since both studies were retrospective, it is possible that the apparent
difference in blood pressure observed may. in part, be explained by
confounding variables between the two periods of analysis, or it may reflect a
statistical error due to the limited sample size.
However. evidence in certain individuals strongly suggested that the
decrease in blood pressure could be attributed primanly to the effects of
amlodipine. and not due to some other unaccounted factors.
For example, in one individual (patient # 15) in the first retrospective
study, the physician in charge believed that the rend transplant patient was
intolerant of nifedipine XL in terms of its effect in controlling blood pressure.
Upon switching the patient to arnlodipine. his mean systolic blood pressure
decreased by approximately 10 mmHg while his mean diastolic blood pressure
was reduced by about 15 mmHg. Since the patient was only receiving
monotherapy for the treatment of hypertension in both analysis periods. one
can quite confidently say that the effect observed can. for the most part. be
attributed to the antihypertensive effect of arnlodipine. Because no other
concomitant antihypertensive medications were given that rnay have differed in
composition and dosage between the two analysis period, this factor can be
eliminated as a cause of the observed decrease in blood pressure with
amlodipine therapy. However. other undetected or uncontrolled for
confounding variables may have played a role in this marginal decrease in
blood pressure.
Although the observed decrease in mean blood pressure of the two
cohorts following amlodipine administration are statistically significant, this
reduction, in each individual cohort, as a whole, is not considered clinically
significant. This holds particularly for the cohort examined in the first
retmspective study where the mean reduction in blood pressure was in the
order of 2 to 3 mmHg The second cohort studied had a mean blood pressure
decrease in the order of 6 mrnHg which is more clinically significanct than
those obtained with the l-lrst cohort.
This observed difference in overall blood pressure reduction may be
attributed to the design of the two retrospective studies. We modified the
amlodipine analysis penod in the second study by examining the
antihypertensive effect of the drug at a later time (i-e., approximately at steady
state). Such a modification of the amlodipine analysis period may explain the
more pronounced decrease in overall blood pressure observed in this cohort.
Another possible explanation for the difference in observed mean
reduction in blood pressure between the two cohorts rnay be due to the fact that
the composition of the patients was more heterogeneous in the first cohort. Six
patients in the first retrospective study were being treated for hypertension
secondary to chronic rend failure. It has been mentioned earlier that the most
difficult type of hypertension to treat is that associated with this condition.
For example, the 23rd patient of the second study had chronic rend
M u r e and exhibited no blood pressure control while on amlodipine with an
increase in both mean SBP and DBP of approximately 15 mm Hg. This change
in blood pressure was more than likely due to a change in the status of the
child's disease than to the inability of amlodipine to lower blood pressure. In
fact. the patient experienced an acute allograft rejection during amlodipine
therapy. This marked change in blood pressure did not reflect the cohort's
blood pressure control. and likely affected the mean blood pressure during
amlodipine therapy.
Since amlodipine provided equal. if not slightly improved blood
pressure control in most of the pediatric patients studied, a physician may not
be inclined to prescribe amlodipine to his/her patients in favour of another
calcium channel blocker if only marginal blood pressure reduction can be
achieved. However. arnlodipine has advantages over other commercially
available calcium channel blockers that make it particularly attractive in
pediatric patients. These main advantages cited by pediatricians (The Hospital
for Sick Children) for the use of arnlodipine in the two patient cohorts
exarnined included once daily dosing, and the availability of a liquid
preparation, thus facilitating the administration of more individudized doses to
a child. This data was collected from the nurses notes and doctor's orders form
in each patient hedth chart.
Although not comrnercially available. such liquid formulations of
amlodipine tablets are readily prepared at the Hospital for Sick Children as
mentioned in the Methods section of the third study (page 48). This liquid
preparation is ideal for younger children who require a long-acting calcium
channel blocker to treat chronic hypertension. but are unable to swallow the
large tablets commercially available (e-,o. nifedipine XL. felodipine ER). These
tablets must not be divided and must be swdlowed intact since both extended-
release formulations of nifedipine and felodipine have mechanisms designed
within their coating which account for their long duration of action. These
mechansims act by delaying absorption of the phmacologically active drug
from the gastrointestinal tract.
One young bone marrow transplant patient examined in the second
retrospective study (patient 1, Table IV), for example. required a long-acting
calcium channel blocker to improve control of his high blood pressure but he
was unable to swallow extended-release tablets of both nifedipine and
felodipine. As a result. the patient was initially given a combination of a short-
acting calcium channel blocker, two diuretics, and a vasodilator. When
amIodipine was later administered as a liquid, the patient's blood pressure was
then treated further with just one diuretic. Without the availability of a liquid
preparation of a long-acting antihypertensive, treatment of this patient's
hypertension would depend on the use of multiple dmgs and complex dosing
schedules that are costly for the parent and inconvenient for the health care
professional and the patient.
In addition. the available dosage forms of the extended-release calcium
channel blockers and amlodipine rnay be to high for a given child's size since
these agents were designed and rnarketed for the adult population. In the case
of the child discussed above the smallest available dose of amlodipine (2.5
mg) was considered too large to initiate therapy since the patient weighed only
11 kg. By preparing a liquid formulation it became possible to adrninister a
clinically accepted dose volume of approxirnately 0.10 mg/kg/day and the
patient was maintained on this daily dose.
As mentioned in the Introduction, single daily dose antihypertensive
agents are preferred because they should provide smooth blood pressure
control for 24 hours with minimal fluctuations in their blood pressure-
lowering effect. Once daily dosing may also prove advantageous in the
pediatric setting because it may improve a patient's compliance. It has been
demonstrated that compliance is inversely related to the number of pills a
patient takes or the number of times a day the patient has to take medication14'.
Furthemore, noncornpliance has been identified as a serious problem in
children who have undergone rend transplantation or who are treated with
dialysis for conditions such as chronic rend failure. Such individuals are
taking numerous medications chronically, and the introduction of a once-daily
calcium channel blocker may improve their compliance 1.50-152 . One should
stress that although extended-release formulations of nifedipine and felodipine
are usually given once a day, it was not uncornmon to see these agents given
twice a day to some of the individuals which were exarnined in the two cohorts.
This contrasts the situation with d o d i p i n e since this dmg is always given
once daily.
In the second retrospective study of bone rnarrow transplanted patients. it
was observed that the number of antihypertensive medications received
decreased in seven patients after amlodipine therapy was started. In six
children, the number of medications remained constant in both periods of
analysis. but increased in only two patients after the introduction of
amlodipine. This reduction in the number of antihypertensive agents given to
most of these children should improve their compliance. Because the patients
presented in these two retrospective studies were hospitalized, compliance
could not be assessed. However, it is of concem when the patient is at home.
Both retrospective studies differed in the adverse event profile observed
during amlodipine therapy. In the first study, no adverse events were recorded
that could be attributed to amlodipine since the event recorded (urticarial rash)
was resolved despite the continuing of administration of the calcium channel
blocker. In contrast, there was a single incidence of d e edema (Le. type of
peripheral edema) in two patients in the bone marrow transplant cohort.
Peripheral edema is the most commonly reported adverse event
associated with amlodipine and has an incidence of 5 6 8 . 5 % in adult men and
14.6- 15% in adult women 151-156 . The adverse events of amlodipine have not
been studied in children.. However, it is possible that this adverse event was
* was caused by amlodipine since the edema subsided a few days after the dru,
discontinued. This form of edema related to arnlodipine in adults does not
appear to result from sodium or water retention and. as a result. usuaily fails to
respond to diuretic treatment'j7 as was the case in the two study children.
The fact that both pediatric patients were withdrawn from amlodipine
therapy shortly after the appearance of ankle edema is of clinical concern since
it suggests that this adverse event may not be well tolerated by children.
Alternatively. the withdrawal of arnlodipine may merely reflect the lack of
physician's experience with this dmg since hekhe may have interpreted this
relatively benign adverse effect in the context of other forms of edema.
In contrast to the situation in children, amlodipine appears to be well
tolerated in adults since this calcium channel blocker is discontinued in less
than 2 % of patients due to the development of peripheral edema'". However.
an assessment of the safety and incidence of amlodipine in children cannot be
made using the information in both retrospective studies since the sarnple size
and assessment period are too small. The reporting of adverse effects is a major
methodological issue in retrospective studies as it may reflect various degrees
of quality of documentation by the medical staff.
Finally. the first retrospective study demonstrated that seven common
semm laboratory constituents remained unchanged before and during
amlodipine treatrnent. When changing from one pharmacological agent
to another, it is usually not desirable if the new dmg drastically changes the
values of these laboratory parameters unless the change is beneficial to the
patient.
Part III:
In contrat to the two retrospective studies. there was no statistical
difference in the overall blood pressure control (both 30 day home and 24-hour
day and night SBP and DBP) between amlodipine and other longacting
calcium channel blockers (Le. nifedipine/felodipine).
Although two individuals of Our cohort refused to participate in 24-hour
ambulatory blood pressure monitoring (ABPM). the results should have
statistical merit since this form of evaluation of antihypertensive treatment has
the advantage of allowing a researcher to use a reduced sample size in
cornparison to the sample size requirements of traditional methods of blood
pressure measurement (e.g. twice-daily re~ordin~s)' ' ' . The sarnple size
requirements are smailer because
between measurements is smaller
measurements during a given day.
the standard deviation of the difference
during ABPM because of more repeated
ABPM is usehl since blood pressure varies considerably during the day.
In fact, blood pressure exhibits a circadian rhythm with a rise in the morning
when a person has awaken (peak at 10 A.M), plateaus during the day, and then
.radually decreases to its lowest value at around 3 A.M''~. Furthemore. it has s
been determined that the occurrence of cardiovascular events (e.g. stroke.
myocardial infarction, and sudden cardiac death) also exhibit a similar
circadian variation and these events occur more frequently during the morning
after one has a ~ a k e n ' ~ ~ .
Ambulatory blood pressure monitoring (ABPM) is a more useful
clinical tool for predicting cardiovascular events associated with hypertension
than other methods of measuring blood pressure. For instance, many studies
have shown that there is a stronger correlation between target organ damage
and ABPM than between intermittent c h i c blood pressure monitoring and
161 target organ damage .
Furthermore, the natural decline in nocturnal blood pressure is absent or
less marked in some renal16', heart 163-165 and liverl? transplants. It has been
postulated that control of noctumal hypertension may help in decreasing target
organ damage such as left ventricular hypertrophy 167.168
It was demonstrated in the rend transplant cohort, as a whole, that
amlodipine and nifedipine/felodipine did not differ in their control of nighttime
blood pressure; however, some individuals in this pediatric cohort had higher
nocturnal than daytime blood pressure during the sarne dmg treatment.
During amlodipine treatment one patient had a higher nighttime than
daytime mean SBP. but with nifedipine therapy had both higher mean
noctumal SBP and DBP. Another patient had a higher mean nocturnal DBP
dunng felodipine than during amlodipine therapy while this same parameter
was higher in another individual dunng amlodipine treatment. Furthermore.
one patient had both higher mean nighttime DBP readings during both
amlodipine and nifedipine treatment.
In a clinical study by Lingens et. which employed 24-hour
ambulatory blood pressure monitoring in 34 pediatric renal transplant patients.
28 patients had noctumal hypertension. Fourteen of these 28 patients were
hypertensive at night but were normotensive during the day. There was also no
difference in antihypertensive or immunosuppressant therapy or in renal
function between those who were hypertensive only at night and those who
were hypertensive during the entire 24 hours.
Our study provides evidence that nocturnal blood pressure elevation is
very common in pediatric rend transplant patients and does not necessarily
have to be accompanied by daytime hypertension. Furthemore, nighttime
hypertension appears to be refractory to antihypertensive therapy in most cases.
Thus, it should not be surprising that some of the 11 rend transplant patients
studied at the Hospital for Sick Children had higher noctumal blood pressure
despite using lonp-acting calcium channel blockers.
Compliance did not differ between the amlodipine and
nifedipine/felodipine treatment pex-iods. In fact. patient compliance (percentage
of the dru; taken by patient versus number of pills prescribed) was very high
during both treatment periods in this pediatric cohort.
However. the high patient compliance observed on both arms of this
study may be an artifact since the study investigator routinely contacted the
families. and hence, there was an intervention here in terms of compliance. It
is likely that without such intervention under normal everyday conditions, the
advantage of a once-daily Iiquid preparation in improving patient compliance
would be evident.
Although there was no evidence of improvement in compliance during
amlodipine treatment when compared directly to other calcium channei
blockers. the second retrospective study suggests that the addition of
amlodipine to an antihypertensive regimen could improve a patient's overall
compliance, because the number of antihypertensive medications used
decreased in about half the patients following the introduction of amlodipine.
1 will now discuss some plausible explanations for the differing results
obtained when both a retrospective and a prospective study were conducted to
evaluate the efficacy of amlodipine.
First. the mean amlodipine dosages used in the first (initial dosage:
0.14 It 0.0 1 mgkgday; maximum dosage: 0.22 + 0.03 mg/kg/day) and second
(initial dosage: 0.12 k 0.01 mgkglday; maximum dosage: 0.16 f 0.02
mg/kg/day) retrospective cohorts were larger than those used by the rend
transplant patients in the prospective study (initial dosage: 0.09 _+ 0.01
mgkg\day; maximum dosage: 0.12 f 0.02 rng\kg\day) . Presumably. higher
doses of amlodipine will provide a more pronounced antihypertensive effect.
Using unpaired t-tests, a sipnificant difference was observed between the first
retrospective study and the prospective study in terms of mean initial and
maximal amlodipine dosage ( p =0.02 and p = 0.04. respectively). However.
there was no significant difference between the second retrospective study and
the prospective study when the two parameters were compared (initial dosage:
p = 0.15; maximal dosage: p = 0.14).
Secondly. the fact that the patients studied in the two retrospective
studies were hospitalized, they likely had more bedrest than the outpatients of
the prospective study. Culmulative bedrest is a factor that may explain the
observed decrease in mean blood pressure observed in the two retrospective
studies.
In addition, the use of adodipine during hospitalization had a temporal
relationship associated with i f since this calcium channel blocker was always
introduced as a second drug after initial antihypertensive therapy. This
temporal trend or "order effect" rnay, in part. explain the statistically
significant reduction in blood pressure during amlodipine therapy that was
demonstrated in the two retrospective studies. but was not observed in the
prospective study.
For instance. it is possible that the hospitalized patients were displaying
"white coat hypertension". White coat hypertension is a persistently elevated
blood pressure measured in the hospital and a normal pressure at other tirnes
(e.g.. at home). Many patients exhibit higher blood pressures when first
hospitalized. but it frequently decreases over time due to environmental ( e . ~ . ,
habituation to the hospital setting) or statistical factors ( e.g., regression to the
nea an)''^. Furthermore, the medical condition for which each patient was
hospitalized rnay have played a role in hisher elevated blood pressure at first,
but as this condition was treated or resolved a reduction in blood pressure may
have followed and coincided with amlodipine treatment. which was always
oiven as second treatinent, E
In the case of the prospective study, the possibility of a temporal
relationship affecting blood pressure was avoided since the study was
cofiducted in a cross-over design involving randomization of treatment. In
addition, there was little or no white-coat hypertension since the patients were
primarily at home for the duration of the study.
Furthemore, a placebo effect may have played a role in blood pressure
reduction when patients were given arnlodipine dunng hospitalization.
Presumably, the placebo effect cannot be discounted in the case of the
prospective study because patients and their parents were encouraged to
participate in the study based on the advantages amlodipine had over their
current choice of calcium channel blocker. However. the use of ambulatory
blood pressure monitoring in the prospective study gives the results obtained
more credibility since it has been documented that this method of blood
pressure measurement reduces the placebo effect"'.
The discussion above cited specific examples of variables that were not
easily controlled for when examining retrospective data. Such factors as
"white coat hypertension" may have been responsible for the difference in
blood pressure control observed between the retrospective studies and the
prospective study.
Potential Advantages of the Retrospective Study Design
On the other hand, retrospective studies done properly have their merits
as well. In cornparison to prospective studies, retrospective studies usually
cost less to conduct and take less time to complete as the data " collects
themselves" ( e g during compassionate use of amlopine in a series of single
patients at Our institution). These types of studies also allow one to extract.
analyze, and draw conclusions on important data that would otherwise be
ignored.
Hospital charts and databases contain useful data on such topics as drug
treatments and surgical procedures. The use of retrospective hospital data as a
source of information is particularly important in the field of pediatric drug
treatment since children. as mentioned previously. have been almost
universally excluded from most short and long-term pharmaceutically-
sponsored clinicai trials.
When a drug, such as amlodipine, is used clinically for the first time in
children at the Hospital for Sick Children, it is. for the most part, reasonably
monitored by the health care professionals to ensure that it has its desired
effects. This is particularly important in the specific case of hypertensive
transplant and nephrology patients since failure of pharmacological treatment
for this condition may have senous repercussions with respect to the children's
long-term health and sumival. Thus, dmg dosing and measurement of blood
pressure is standardized and recording of such parameters is quite meticdous.
As a result. conclusions drawn from this relatively accurate source of
retrospective data have merit and cari serve as an impetus for future prospective
clinical pharmacological studies in the pediatric population.
Finally. the second retrospective study provided insightful information
regarding the safety of arnlodipine that was not observed in the prospective
study. With this information on safety. pediatricians will be more often well-
informed to deal with this possible safety issue (Le., intolerance to ankle
edema) when it becomes more widespread as amlodipine use increases in the
pediatnc population.
6. CONCLUSION:
Taking into consideration that there are confounding variables present
when drawing conclusions from retrospective studies, both studies provided
evidence that amlodipine is at least as effective as baseline treatment in
controlling pediatric hypertension in transplant patients and individuals with
underlying renal abnormalities. These conclusions were verified when a
prospective study was conducted of renal transplant patients. In this study.
amlodipine provided similar blood pressure control to nifedipine or felodipine
when two distinct methods of measuring the blood pressure were applied. The
prospective study also provided evidence that patient compliance during
amlodipine was equal to that of other long-acting calcium channel blockers.
Finally, al1 three studies demonstrated that short-term arnlodipine therapy was
oenerally tolerated by pediatric patients since there were very few adverse e
events reported. Since amlodipine is as effective as other once-daily calcium
channel blockers in pediatric patients, it should becorne the drug of choice for
treatment of hypertension in this population since it has unique properties
which are advantageous to children. These properties include once daily
dosing, and the availability of a liquid preparation of this calcium channel
biocker allowing precise dosing and an ability to administer more appropriate
dosages of the drug to pediatric patients.
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8. APPENDICES
1. A paper summarizing the retrospective study of the eficacy and safety of
amlodipine in pediatric bone marrow transplant patients has been accepted for
publication in the scientific journal Chical Pediarrics (Cleveland, Ohio) and
is currently in press.
2. A paper summarizing the retrospective study of the efficacy and safety of
amlodipine in pediatric transplant and nephrology patients has been submitted
to the journal Pediatrics.
3. A paper has been submitted to the Journal of Pediatrics which summarizes the
antihypertensive amlodipine in pediatric rend transplant patients.
Amlodipine Therapy for Hypertension in Pediatric Patients
Douglas L. Blowey MD1, John W. ~ o ~ a n ' , Elizabeth Harvey MD~, Gerald S. Arbus MD', Paul 1. Oh M D ~ ,
Gideon Koren MD'
Divisions of Clinical Pharmacology and ~ o x i c o l o ~ ~ ~ , and Pediatric ~ e ~ h r o l o ~ ~ ' at The Hospital for Sick Children,
University of Toronto, Toronto, Ontario, Canada.
Division of Clinical ~ h a r r n a c o l o ~ ~ ' at the Sunnybrook Health Science Centre, University of Toronto, Toronto, Ontario,
Canada
Supported by a grant form Mzer Canada Inc., Kirkland Quebec
Abstract
Obiective: Arnlodipine is a new calcium channel blocker with potential for
increased utility in children
due to the unique phsiochemical properties of water solubility and prolonged
intrinsic half life permitting once-a-day administration. The drug has not been
previously evaluated in children.
Study design: We retrospectively evaluated the first 23 children who either
converted from another calcium channel blocker to amlodipine or had
amlodipine added to their antihypertensive regimen in Our institution.
Results: Amlodipine was at least as effective as standard antihypertensive
therapy in maintaining target systolic and diastolic blood pressure. For both
values, there were statistically lower pressures measured with arnlodipine (after
dose titration) as compared to the baseline (2.5 f 1.1 mm Hg lower for systolic
and 3.1 I 1.5 mm Hg for diastolic. p < 0.05). No clinical or laboratory adverse
effects were documented.
Conclusion: Amlodipine is safe and provides similar. if not slightly improved
blood pressure control in children receiving pharmacological treatment for
hypertension. Because of its prolonged elirnination half life and the ability to
oive it in solution, amlodipine has advantages which should be considered by 2
pediatricians treating children with hypertension.
Introduction
The pharmacological treatment of hypertension in children frequently includes
a calcium channel blocker [ [ [ 1.2 1. Therapeutic options are often Iimited in
children by the impracticality of the commercially available calcium channel
blocker formulations. Cornmonly, tablets and capsules are too large to be
swallowed by children or the dosage forms available are excessive.
Amlodipine (Pfizer, Kirkland Quebec), a new dihydropyridine class calcium
channel blocker, possesses unique physiochemical properties [ 3 ] which makes
it potentially attractive for use in children. Unlike the extended release calcium
channel blockers that prolong their blood pressure lowering effect by
controlling the rate of drug absorption. and hence require the dose form to be
ingested intact, the extended antihypertensive effect of amlodipine results from
its slow elimination half life ( e.g, TI,? 2 30 hours). The fact that amlodipine's
extended action is not contingent upon an intact delivery systern permits the
tablet of amlodipine to be fractionated or dissolved into a liquid suspension
prior to dosing. Despite these potential benefits, amlodipine has not been
evaluated in children with hypertension.
In an attempt to evduate the eîficacy and safety of amlodipine in pediatric
patients, we report our experience with children who were either converted
from another calcium channel blocker to amlodipine or had amlodipine added
to their antihypertensive therapy at The Hospital for Sick Children. Toronto.
Canada.
Methods
Pharmacy records were reviewed to identify patients who received amlodipine
between July 1993 and July 1995. For each patient the information gathered
before and after the onset of amlodipine therapy included: age: diagnosis most
likely related to the hypertension; reason for choosing amlodipine; temporally
related adverse reactions; systolic blood pressure (SBP) and diastolic blood
pressure (DBP) measurernents obtained during hospitalization or in an
outpatient c h i c : concurrent medication and dosage: semm creatinine.
hemoglobin, hematocrit, platelet count, leukocyte count, sodium. and
potassium.
The mean SBP and DBP measurements for each analysis period, that is, before
amlodipine and during amlodipine therapy (after dose titration) were used for
cornparison. To be included in the analysis, at least 3 separate blood pressure
readings for each observation period were required. Statistical cornparisons
were performed using a Student's paired t-test. Unless otherwise specified the
data are presented as mean f SEM.
Results
Patient Characteristics: (Table 1)
Twenty three of the 28 patients identified by pharmacy records had su:
blood pressure data before and during arnlodipine therapy to be included in the
analysis (21 patients for DBP). The median age was 7 years (range: 2 weeks to
17 years) and 16 were males. Al1 patients were receiving antihypertensive
medications prior to the initiation of amlodipine. Amlodipine was used as a
substitute for other calcium channel blockers (Le.. nifedipine or felodipine) in
19 of the 23 cases and replaced hydralazine and enalapril in 1 patient each. In
2 cases amlodipine was added to a diuretic or p-blocker. The average
amlodipine dose used to initiate therapy was 0.14 mgkg (range, 0.05 to 0.24).
Ten (43%) patients required an increase in the amlodipine dose resulting in a
mean maximal dose of 0.22 mgkg (range, 0.08 to 0.66).
Blood Pressure: (Table II)
The SBP and DBP were significantly lower during amlodipine therapy (after
dose titration) compared with baseline (2.5 I 1.1 mm Hg and 3.1 f 1.5 mm Hg,
respectively: p c 0.05). When the 3 patients with a clinically relevant decrease
in the dose of prednisone ( >5 mg) or cyclosporine ( > 10% decrease from
baseline) between the two observation periods were removed from the analysis,
the mean SBP and DBP decreased by 2.6 I 1.3 mm Hg and 2.9 + 1.7 mm Hg,
respectively (p = 0.05 and 0.1 1).
Laboratory Data: (Table III)
There were no significant changes in semm sodium, potassium, creatiriine.
leukocyte count. platelet count, hemoglobin, or hematocrit with arnlodipine
therapy. There was a clinically nonsignificant downward trend in the leukocyte
count and upward trend in the serum potassium.
Adverse Drue Reactions:
There were no adverse reactions temporally related to arnlodipine therapy.
Discussion
This analysis demonstrated a slight lowenng of the SBP and DBP in children
with treated hypertension when the andodipine was substituted for other
antihypertensive medications or added to the antihypertensive regimen. The
observed decrease in blood pressure during amlodipine may reflect
uncontrolled difference between the observation periods such as blood
pressure measurement technique,
the placebo effect, superior pharmacodynarnic effect of amlodipine, improved
ability to titrate the dose of
dod ip ine , or improved cornpliance with the once-a-day dosing of amlodipine
solution. Included in the many factors which may effect blood pressure are the
medications prednisone and cyclosporine. Although there was a downward
trend in the SBP and DBP when the 3 patients with clinically relevant changes
in cyclosponne or prednisone were excluded. the statistical significance was no
longer present. The change in statistical significance most likely represents a
limitation of our sarnple size and the clinically diminutive change in blood
pressure rather than an effect of the medications themselves as the average
decrease in SBP (1.5 mm Hg) and DBP ( 1.4 mm Hg) for the 3 excluded
patients is less than the observed decrease for the study cohort (SBP: 1.5 mm
Hg: DBP: 3.1 mm Hg).
In the rnajonty of patients (83%) amlodipine was substituted for another
calcium channel blocker. Availability of a liquid medication. ability to
prescribe small doses, and once-a-day dosing were the predominant reasons
oiven for the use of amlodipine.
Arnlodipine is available in 2.5, 5 (scored), and 10 mg tablets. Although
amlodipine is water soluble, an oral solution is not commercially available.
The current practice for preparing a liquid dose of adodipine at the Hospital
for Sick Children is to dissolve a 5 mg tablet in 5 mL of water using a dose
container irnrnediately prior to the dosing period. The appropriate dose is
given using a syringe and the remainder is dicarded. A new solution is
prepared for each dose. There is no information available concerning the
stability and eficacy of dissolved arnlodipine. The typical dose, extrapolated
from the weight adjusted adult dose, used to initiate amiodipine therapy is 0.10
to 0.15 mgkg given once daily. The dose does not need to be adjusted for
rend insufficiency [ 4 ] because the drug is mainly biotransformed to inactive
metabolites,
Nurnerous reports in adult patients with hypertension have shown amlodipine
to be safe and effective in the treatment of hypertension [ 5,6 1. Although
reorted to occur Iess frequently, adverse effects of arnlodipine are similar to
those reported for other calcium channel blockers consisting of flushing,
headaches, edema, and dizziness [ 5 1. in a small percentage these adverse
events were severe enough to warrant withdrawal of the drug. In Our series of
23 patients there were no adverse events associated with amlodipine therapy.
However, a single patient identified by the seaich of pharmacy records, but not
included in the analysis because of insufficient data, developed a urticarial rash
during arnlodipine therapy which resolved despite the continuation of
amlodipine. Similar to the adult experience. there were no significant changes
in the laboratory values reviewed.
We conclude that arnlodipine is safe and provides similar. if not slightly
improved blood pressure control in children receiving pharmacological
treatment for hypertension.
References
1. Sinaiko AR. Treatrnent of hypertension in children. Pediatr Nephrol 1994:
8: 603-609.
2. Baluarte HJ. Gruskin AB, Ingelfinger JR. Atablein D. Tejani A. Analysis of
hypertension in children post rend transplantation-a report of the North
American Pediatric Renal Transplant Cooperative Study
(NAPRTCS). Pediatr Nephrol 1994; 8: 570-573.
3. Meredith PA. Elliott HL. Clinical phmacokinztics of amlodipine. Clin
Pharmacokinet 1992: 22: 22-3 1.
4. Laher MS. Kelly SG, Doyle GD, et al. Phamlacokinetics of arnlodipine in
rend impairment. J Cardiovasc P h m a c o l 1988; 12(suppl 7): S60-S63.
5. Cross BW. Kirby MG, Miller S , Shah S, Sheldon DM. Sweeney MT. A
multicentre study of the safety and efficacy of amlodipine in mild to moderate
hypertension. Br S Clin Pract 1993; 47: 237-240.
6. Mroczek WJ, Bums JF, Allenby KS. A double-blind evaluation of the
effect of arnlodipine on ambulatory blood pressure in hypertensive patients. J
Cardiovasc Pharmacol 1988; 12(suppl7): S79-S84.
Table 1: Patient Characteristics
Patient Age Gender Diagnosis
Number (Y rs 1
Antihypertensives AmIodipine
Prior to Andodipine Dose(mg/kg/d)
InitialLMav
Chronic Rend Failure
AHUS
Rcnal Transplant
BPD
Chronic Rend Failurc
Bone Marrow
Transplant
Har t Transplant
ECMO
Hcart Transp lan t
Chronic Renal Faiiure
Rend Transplant
Rcnal Transplant
Bonc M m o w
Transplant
Rcnal Artcy Stcnosis
Renal Transplant
Chronic Rcnal Failure
Hcart Transplant
Rcnal Transplant
Gl«mcrulonephritis
Rcnal Transplant
Chronic RenaI Failurc
Rcnal Transplant
Chronic Rend Failure
Furoscmidc
Fcladipine*
Nif-PA*. Nadolol*
Hydralrizine*. HCTZ
NiC-SA*. Captopril*
Labctolol*
Ni(-SA*. Furosemide
Nif-SA*
Nif-SA*
Nif-SA*. Captopril*
Nif-XL*
Nif-SA*
Nif-PA*
Nif-PA*. Nridolol. HCTZ
Nif-XL*
Nif-SA*
Enalapril*. Furoscmidc
Nif-XL*
Nif-PA*
Nif-PA*
Nif-Xi... . Hydralazine
Nif-PA*
Nif-PA*. Hydralazinc - - - - - -
* discontinued with arnlodipinr thcnpy; Nif. nifedipine: SA. short-acting: PA. prolonged action: XL. extended release; HCTZ. hydrochlorothiazide; ECMO. extracorporeal membrane oxygenation; BPD. bronchopulmonary dysplasia; AHUS. atypical hemolytic uremic syndrome
Table II: Blood Pressure (mean k SEM)
Before Amlodipine During Amlodipine p-value
(mm Hg) (mm Hg)
Al1 Patients
SBP (23) 126.7 + 2.9
DBP (21) 80.2 i 2.4
Patients with consistent
Pred and CSA dose
SBP (20) 125.8 f 2.9 123.2 I 2.6 0.05
DBP (18) 80.7 +_ 2.6 77.8 + 2.9 0.11
Before Amlodipine During p-value
Adodipine
(n=18)
(n=lS)
Sodium (mmoVL) 137 k 0.8 137 + 0.6 > 0.05
Potassium
(mmoVL)
Creatinine
(pmoJm
WBC ( 1 0 ~ ~ )
Platelets (lo9/L) 282 4 45.8 280 .+ 40.4 > 0.05
Hemoglobin (g/L) 109 k 4.1 106 t 3.9 > 0.05
Hematocrit ( % ) 33 -t 1.3 32 t 1.2 > 0.05
W C . white blood cells (leukocytes)
1 O9
The Efficacy of AmIodipine in Pediatric Bone Marrow Transplant Patients
Sohail Khattak M.D' .. John W. ~ o ~ a n ' ,
E. Fred Saunders M.D.?. Jochen G.W. Theis M.D.',
Gerald S. Arbus M.D.~, Gideon Koren M.D.'
From the Division of Clinical Pharmacology and ~ o x i c o l o ~ ~ ' , the Division of Hernatology and 0ncology2 and the Division of ~ e ~ h r o l o ~ ~ ' ,
The Hospital for Sick Children,Toronto: The University of Toronto, Ontario. Canada
Key words: amlodipine, bone marrow transplant, blood pressure
Supported by a grant from Pfizer Canada Inc.. Kirkland Lake, Quebec
Address for correspondence: Gideon Koren, MD, ABMT, FRCPC Division of Ciinical Pharmacology and Toxicology Department of Paediatrics The Hospital for Sick Children 555 University Avenue Toronto, Ontario. CANADA M5G 1x8 Tel: (416) 813 -5781 Fax: (4 16) 8 13 - 7562
Abstract
The calcium antagonist amlodipine may have the potential for expanded use in children due to its physiochernistry and pharmacokinetic profile that facilitates once-daily dosing in a liquid formulation. Its safety and efficacy have not been previously evaiuated in children. A retrospective analysis of 15 pediatric bone marrow transplant patients who had amlodipine incorporated into their antihypertensive dmg regirnen reveal significantly lower blood pressure as compared to baseline therapy [123.5 f 2.1 mmHg and 117.2 + 2.2 mmHg (systolic blood pressure before and dunng amlodipine; p< 0.05); 8 1.5 f 1.8 mmHg and 75.5 k 2.6 rnrnI-Ig (diastolic blood pressure before and during amlodipine; p c 0.05)]. Amlodipine provided improved blood pressure control in this cohort and may provide a valuable pharmacological alternative for treatment of pediatric hypertension.
Introduction
In children hypertension may comrnonly arise from pathophysiological processes affecting the renovascular, rend parenchymal, cardiovascular and endocrine systems or may be dmg-induced. This contrasts the situation in adults where the etiology of this disease is usually unknownl-'. In bone marrow transplant patients, the potent immunosuppressant agent cyclosporine used for oraft-versus-host disease prophylaxis and treatment is associated with an increased b
prevalence of hypertension. Hypertension develops shortly after initiation of cyclosporine therapy and its incidence can be further increased by the addition of corticosteroids to immunosuppressant therapy5".
Calcium antagonists are commonly administered to treat hypertension in children, whether as monotherapy or in combination with other pharmacological agents. However, the commercially available calcium antagonist formulations in use (eg. nifedipine, felodipine) are designed for adults and their use is limited in the pediatric population. Typically, tablets or capsules of such antihypertensives are too large to be swallowed by young pediatric patients andor the dosage sizes available may be too excessive for a given child's size.
Amlodipine is a relatively new calcium antagonist of the dihydropyridine class which possesses unique physiochemical properties of prolonged intrinsic elimination half-life and water solubility which set it apart from other dihydropyridine-based antagonists, and rnay offer advantages to pediatric patients. These unique properties facilitate once-daily dosing in a liquid preparation. The objective of this study was to describe the efficacy of amlodipine in children, by analysing Our institutional experience with pediatric patients who were administered amlodipine as part of their pharmacological treatment for hypertension secondary to bone marrow transplantation.
Methods
Fifteen pediatric bone marrow transplant patients who were treated with amlodipine were identified by hospital pharmacy records. Patient chart reviews were performed and the penod of analysis of antihypertensive therapy ranged from May 1994 to June 1996 and encompassed periods before and during amlodipine treatment. Al1 identified bone marrow transplant patients were administered amlodipine at some point dunng the aforementioned period of analysis. The following information was extracted for each patient: gender: age: weight; diagnosis responsible for bone marrow transplant; indications for amlodipine; types and doses of medications given before and during amlodipine therapy; systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurements; and adverse events recorded during amlodipine treatment.
The mean SBP and DBP measurements of each patient were used for cornparison of efficacy of the two treatment periods; before and during adodipine therapy. The length of the analysis period prior to arnlodipine treatment was confined to the 3 days pnor to the initiation of amlodipine since this was likely the period when the patient was hypertensive and the physician was deciding to substitute amlodipine for another blood pressure lowering agent or to incorporate this calcium antagonist into the antihypertensive regimen. The amlodipine treatment analysis penod was set from the fifth day and on from the commencement of amlodipine therapy since it typically takes approximateky five half lives for steady state levels of the medication to be reached in the circulation and hence a maximal effect on blood pressure to be encountered.
Blood pressure measurements were obtained in Our institution by V ~ ~ O U S
bone marrow transplant ward nurses using a Dinamap rnonitor with a Dura cuff (Medicare Inc.) or a Hewlett Packard electrocardiogram unit with calibrated V- Lok cuffs (W.A. Baum Co., Inc. U.S.A.) Typically, blood pressure measurernents are recorded six times per day. Manual blood pressure measurements with a Tycos sphygmomanometer were used on occassion to confirm the accuracy of a given measurement. The nurses were not blinded to the antihypertensive medications each patient received. The data in the results are presented as mean k SEM. and statistical cornparisons of blood pressure before and during amlodipine therapy were conducted using Student's paired t-tests.
Resuits
Patient Characteristics:
The median age for Our patient cohort was 8 years (range: 1 to 17 years) and 9 were fernales. Al1 patients were administered amlodipine orally once daily. Four of the younger patients received amlodipine in the form of a liquid preparation in an attempt to match the dose to their weight. The average initial dose of arnlodipine used in antihypertensive therapy was 0.12 mg/kg/day with a mean maximum dose of 0.16 mg/kg/day (Table 1). The recomrnended initial dosage of amlodipine for adults is 0.10 mg/kg/day. Four patients had their arnlodipine dosage increased while one patient was given a loading dose twice the corresponding maintenance doses. The percentage increase in amlodipine dose and frequency of dose changes varied in each of the four patients and was based on a clinical decision by the specific hematlogist/oncologist in charge of each patient.
In the majority of our patients, the onset of hypertension was following transplantation while one patient diagnosed with neuroblastoma experienced hypertension prier to receiving a bone marrow transplant.
BIood Pressure:
Eleven of the fifteen patients (73 %) had an overall individual reduction in both systolic and diastolic blood pressure after amlodipine therapy was initiated. Both the SBP and DBP were significantly lower in our patient cohort during amlodipine therapy when compared with baseline therapy (6.5 +. 2.7 mmHg and 5.9 k 2.7 mmHg. respectively; p< 0.05) [Table 21.
Adverse D r w Events: Two patients experienced ankle ederna during amlodipine which led to
discontinuation of the dmg in both cases.
Discussion
Our retrospective analysis demonstrated both statistically and clinically significant reductions of both SBP and DBP in children undergoing
pharmacological treatment for hypertension when amiodipine replaced one or more antihypertensive medications or was added to an existing antihypertensive regimen. Since this is a retrospective study the apparent difference in blood pressure may reflect also a placebo effect, uncontrolled changes in variables between the two analysis periods, or an error due to Our limited sample size.
In a few of the 11 patients that experienced a overall decrease in blood pressure the reduction was minimal. In two patients (Ml , #15) with normal blood pressure, arnlodipine replaced a single antihypertensive agent which was adminstered more than once-a-day. This practice is very common in our institution so as to provide a more convenient dosing schedule for our patients and it helps to improve cornpliance. However. this cohort, as a whole, had a significant reduction in blood pressure during amlodipine therapy as compared to the analysis period p io r to the introduction of this calcium antagonist.
One problern which we identified was the variation in the magnitude and frequency of amlodipine dose changes ordered by various staff pediatricians. In a few children, the amlodipine was increased several times without allowing this calcium antagonist to reach steady state concentrations at a given dose. We suggest in the future that pediatricians take the pharmacokinetic properties of arnlodipine into account and only increase the dose of this agent if blood pressure control is insufficient after approximately one week. Two patients (#9, #14) in Our cohort that experienced an increase in mean blood pressure during amlodipine were subject to this dosing dilemma. This oversight may have hindered a proper assessrnent of the ability of amlodipine to control each patient's blood pressure.
The main advantages of amlodipine included the availability of a liquid formulation, an improved ability to administer more appropriate doses to the child. and once-daily dosing. These properties of amlodipine result from physiochernical properties that are not possessed by other dihydropyridine calcium antagonists. Firstly, the amlodipine molecule exists primanly in an ionized form at physiological p ~ 7 and has high water solubility. As a result, amlodipine can be converted into a liquid by dissolving the tablet dose in water. Although there is no commercially available liquid formulation of arnlodipine Our institution's pharmacy provides a dissolvant dose container so that a liquid preparation of the dnig can easily be created. This liquid preparation is administered to children who cannot swallow other calcium antagonjst capsules and tablets (eg. extended- release nifedipine) or is used to optimize a child's dose.
Furthermore, in adults, arnlodipine' s intrinsic elimination half-life (53 k 14 hours)%s significantly prolonged when compared to other calcium antagonists9. This profile allows for once-daily dosing in children and results in smooth daily blood pressure control without major fluctuations in peak-trough concentration^'^. In contrast to amlodipine, the extended-release calcium antagonists (egnifedipine, felodipine) provide once-daily dosing and prolonged blood pressure reduction via a mechanical control of the rate of absorption which relies on an intact delivery system. As a result, the available dosage forms of such dmzs cannot be broken down to tailor it for a child's weight specifications.
In the specific case when arnlodipine replaces a calcium antagonist administered more than once-daily ( e g nifedipine PA), the switch rnay improve long term patient compliance. It has been demonstrated that compliance is
I I inversely related to the number of pills taken by the patient . Although compliance is not an issue in our patient sample because they were al1 hospitalized while receiving their blood pressure medications, it is an area of concern when the patient is at home.
Upon initiation of amodipine therapy, it was found that the number of antihypertensive medications decreased in 7 patients when compared to the antihypertensive regimen pnor to amlodipine. In 6 individuals, the number of medications remained constant in both analysis penods and only increased in 2 patients during amlodipine treatment.
Numerous studies in adults have shown arnlodipine to be as effective and safe as monotherapy in the management of patients with mild to rnoderate severe
12-15 hypertension . Furthermore, adult clinical trials have demonstrated that amlodipine is effective and generally safe when used in combination with other antihypertensive drugs. Amlodipine potentiates the eficacy of diureticsI6, B-
19.20 blockers "-18, ACE inhibitors and other calcium antagonistsY .
The adverse event profile of amlodipine in adults is sirnilar to that of other calcium
79-24 antagonists-- . However, in studies where the dosages were titrated to provide therapeutically equivalent reductions in blood pressure, it was found that there were less withdrawals of amlodipine therapy due to adverse events compared to nifedipine PA"'. nitrendipineZ5, and felodipine 26.
In adults, ederna represents the highest overall incidence of side effects with amlodipine but is rnild in nature and rarely warrants drug cessation. Specifically, there was a 9.8 % incidence of ankle edema during arnlodipine therapy in an adult sample investigated by Osterloh et al2'. Ankle edema was observed during amlodipine therapy in Our study. However, we could not rnake any conclusions about the incidence of this adverse event in children due to our srna11 sample size.
In conclusion, in pediatric bone mmow patients amlodipine provides equd if not better blood pressure control when it is added to a antihypertensive regirnen or used as replacement therapy for treatment of hypertension. Amlodipine may be better suited for pediatric treatment of hypertension than existing calcium antagonist therapy because of once-daily dosing, the ability to
administer more individualized doses, and the option of adrninistering a liquid preparation. A future prospective study comparing the efficacy and safety of arnlodipine to standard antihypertensive treatment would be useful to control for sorne of the confounding variables present in this study and is currently in progress at Our institution .
Table 1: Characteristics of Pediatric Bone Marrow Transplant Patients
Patient Gender 4 ! e Weight Diagnosis Amidipine Dose
Nurnber (Yrs) (kg) ( m g / k d d ~
Ini tial\Maximurn
I k1 1 I I Severt: Combined 0.09\0.09 Irnrnunodt.ftïciency
Xcutc Lymphoblristic Lcukrmiri
Chediak-Higashi Syndrome
Sevcrc Combined Immunodeiiriency
Hurler's S yndromc
Neurobtristomri
Fltnconi's .L\ncmia
Aplristic Anemia
Aplifiisric Ancmia
Chronic ,Myelogenous Leukemia
Schwachrnm-Diamond Syndrome
Aplris~ic Anemiri
Acute Myclogenous Lcukcmia
Acutr: Lymphobiristic Leukcmia
Xcutc Lymphoblrtstic Leukemia
- Patient Numbe~
- 1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Mean -
Table 2: Mean Patient Blood Pressure Before and During Amlodipine Therapv
Post-amlodipine SBF (mmHg)
Post-amiodipine DBP (mrnHg)
SBP= Systolic Blood Pressure DBP=Diastolic Blood Pressure
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THE EFFECTIVENESS OF AMLODIPINE IN PEDIATRIC
HYPERTENSION; A RANDOMIZED PROSPECTIVE,
CROSSOVER TRIAL
John W. Rogan Msc, Douglas Blowey MD, Sohail Khattak MD,
Gerald S. Arbus MD, Gideon Koren MD
From the Divisions of Clinical Pharmacology/ Toxicology and Nephrology,
The Department of Pediatrics and Research Institute,
The Hospital for Sick Children, Toronto,
Departments of Pediatric Pharmacology, Pharmacy & Medicine,
University of Toronto
Address for Correspondence:
Gideon Koren, MD, ABMT, FRCPC The Hospital for Sick Children 555 University Avenue Toronto, Ontario Canada M5G 1x8 De partment of Paediatrics Divison of Clinical Pharmacology and Toxicology Tel.: (416) 813-5781 Fax: (416) 813-7562
ABSTRACT:
A prospective study in a crossover design was conducted at the Hospital for Sick
Children on 1 1 nephrology patients (10 had received rend transplants) to compare
the efficacy and compliance of amlodipine to that of other long-acting calcium
channel blockers (i.e. felodipine or nifedipine). Utilizing Student's paired t-tests.
no significant difference was observed in mean systolic blood pressure (SBP) and
diastolic blood pressure (DBP) between each 30 day calcium channel blocker
treatment (p = 0.09 , p = 0.27, respectively). It was also demonstrated using 24-
hour blood pressure monitoring that there was no significant difference between
each dmg treatment period in both mean day time (p =0.78) and nighttime SBP (p
= 0.96), and also in mean day time (p =0.65) and nighttime DBP (p = 0.95).
Furthemore. patient compliance was similar in both the amlodipine and the
nifedipineWelodipine treatment period (p = 0.94). This data suggests that
amlodipine provides comparitively effective monthly and 24-hour blood pressure
control in pediatric nephrology patients as that of other long-acting calcium
channel blockers. However, amlodipine may be ideally suited for treatment of
pediatric hypertension since it is the only calcium channel blocker which can be
administered once-daily as a liquid preparation.
INTRODUCTION:
The incidence of pediatric hypertension has been estimated at between 0.86
and 98'* ' and this disease has been attributed to underlying renal parenchymd
abnormalities in 70% of the cases in a study of children under 10 years of age3.
Hypertension is a frequent complication in rend transplant patients' and
may be caused by multiple factors which include intact native kidneys, renal artery
stenosis, acute and chronic rejection, recurrence of the original renal disease, and
dmgs ( eg. cyclosporine and cortico~teroids)~.~.
Post-transplantation hypertension is a serious clinical problem since there is
evidence that it is associated with a significant decrease in allograft surviva17-"nd
the disease is the most important risk factor for cardiovascular morbidity and
mortality in transplant patients10. Hypertension following renal transplantation
appears to be more cornmon in children than adultsl l .
Since the introduction of cyciosporine as an irnrnunosuppressant, the
incidence of hypertension following renal transplantation has risen frorn a range of
12-19 45% to 50% to a range of 67% to 86% . Furthemore, the nature of
pharmacological treatment for this disease has changed following the use of this
imrnunosuppressant agent since the renin-angiotensin system appears now to play
a minor role in the pathogenesis of hypertension'0. Cyclosporine causes afferent
arteriolar vasoconstriction and this is believed by rnany to be the primary
71 7 7
mechanisrn by which this agent causes hypertension- *--.
Calcium channel blockers are considered an ideal first-line agent for the
treatment of post-transplantation hypertension 23-25 since they can partially
counteract the rend vasoconstrictive effects of cyclosponne'6~32 and have been
shown and postulated to mediate renal protection through various mechanisrns3-'.
Calcium channel blockers are used frequently in hypertensive children since
there are relatively low rates of adverse effects at low to moderate doses but there
is insufficient information describing the efficacy and long-term safety of these
antihypertensive agents3". AmIodipine is a relatively new dihydropyridine-based
calcium channel blocker which may be ideal for first-line treatrnent of pediatric
post-transplantation hypertension since it can be administered once-daily as a
Iiquid preparation. Since there is no data on the efficacy of amlodipine in
children, a comparative prospective study of pediatric renal transplant patients
was conducted by us to address this issue.
METHODS:
Patients
Eleven patients between nine and seventeen years of age who were
receiving a calcium channel blocker (i.e. nifedipine or felodipine) for treatment of
hypertension were recruited from the nephrology outpatient c h i c at Our
institution. Ten of the patients had previously received a rend transplant.
Patients were included in the study if their transplant occured at least three months
prior to their recruitment and they exhibited stable blood pressure control (Le. no
changes in dosage and type of antihypertensive therapy) one rnonth before
recruitment. Patients were excluded if they had a known allergy to calcium
channel blockers. The study protocol was approved by our institution's research
ethics board.
D N ~ Treatment
In a randornized crossover design, each patient received amiodipine and
nifedipine (or felodipine) in two separate 30 day treatment periods. For example.
if the patient was randornized to receive nifedipine in the first treatment period,
he\she would receive amlodipine in the second treatment period. There was no
washout period between treatment periods for ethical reasons. Amlodipine was
administered as an oral suspension once-daily at an approximate initial dose of
0.10 mgkg. The maximum initial dose permitted was 5mg. If the patient's blood
pressure was not in the nomotensive range (i.e. below the 95th percentile for age
and gender) following one week of therapy, the staff nephrologist raised the
dosage by 508 to 100% to a maximum of 10 mg. The primary investigator was
blinded to any changes in dosage. The dosage of either nifedipine or felopine
oiven as tablets was unchanged during the study and was previously titrated by the a
staff nephrologist prior to the study so that the patient's blood pressure was in the
normotensive range for age and gender.
Blood Pressure Measurement
Blood pressure was monitored twice daily at home by an adult caregiver
using either a mercury sphygmomanometer or an automated oscillometric device
(Critikon Inc., Tampa Fla.). The caregivers were trained by the staff nephrology
nurses to obtain blood pressure measurements using a standardized technique and
appropriate blood pressure cuff size(4 from thesis 2nd Task Force). The patient
had blood pressure recorded using the same arm while in the supine position.
Ambulatory blood pressure was recorded over a 24 hour penod during the last
week of each treatment period using a Takeda blood pressure monitor mode1 TM
2420 (A & D Engineering Inc., California) or an ambulatory blood pressure
rnonitor mode1 90207 (Spacelabs Medical. Mississauga, Ontario). Each monitor
was preset to measure blood pressure every half hour during the day (9 A.M. to 10
P.M.) and each hour during the night (10 P.M. to 9 A.M.).
Compliance
Compliance was assessed using the Medication Event Monitoring System
(MEMS, Aprex. California). The MEMSO TrackcapTM is a medication bottle
cap which contains microelectronic a microelectronic tracking device. The
electronic chip in the lid of the cap recorded the date and time a medication bottle
containing each snidy dmg treatment was opened by the patient. The parents and
child were unaware of the purpose of this electronic monitoring device.
Adverse Effects
Patients were instructed to record any adverse events which may have
occured during each 30 day treatrnent period.
Statisicd Analysis
With mean diastolic blood pressure as a primary endpoint. a sample of
eleven patients was sufficient to show a median effect size difference in blood
pressure between the two dmgs with an alpha of 0.05 and a power of 80%. An
effect considered clinically significant was any value greater than 10 mm Hg.
Amlodipine was compared to nifedipine and felodipine with respect to: mean 30
day systolic blood pressure (SBP) and diastolic blood pressure (DBP), mean 24
hour SBP and DBP during both the day and night, and the rate of cornpliance
(percentage of dmg taken versus prescribed amount). Al1 cornparisons were
performed using a Student's paired t-test. Data are presented as mean I SEM.
RESULTS:
Pediatric Patient Charactenstics (Table 1):
The median age of the cohort was 16 years (range: 9 to 17) and included six
males and five females. The mean initial dose of arnlodipine used to initiate
therapy was 0.09 I 0.01 mg\kg\day. Four patients required an increase in
amlodipine dosage so that the mean maximal arnlodipine dose was 0.12
mg\kg\day. Six patients were treated with a single calcium blocker throughout the
study while the remaining individuals had combination therapy for treatment of
their hypertension. The additional antihypertensive agents used by these five
Des were patients were not of the calcium channel blocker class and their dosa,
identical in each treatment phase of the study.
Blood Pressure Control:
1. Mean 30 Day Blood Pressure (Table II):
There was no significant difference in both the cohort's mean 30 day SBP
and DBP when comparing the two treatrnent periods. Eight patients had an
individual rnean reduction in SBP durhg amlodipine therapy while six patients
experienced a lower mean DBP during this treatment period.
2. Mean 24 Hour Blood Pressure:
a) Dav time:
No significant difference was evident in cohort mean day time SBP
(amlodipine: 126.6 f 3.4; nifedipine\felodipine: 127.5 f 3.4: p = 0.78) and DBP
(amlodipine: 78.6 f 2.2; nifedipine\felodipine: 77.5 f 2.2; p = 0.65).
b) Niohtirne:
No significant difference was found between each dmg treatment period in
both cohort mean nighttime SBP (arnlodipine: 1 19.5 f 2.9; nifedipinelfelodipine:
1 19.3 I 3.3; p = 0.96) and DBP (arnlodipine: 74.7 k 3.2; nifedipinelfelodipine:
74.5 I 3.4; p = 0.95).
Cornpliance:
There was no significant difference in mean cornpliance (Le. percentage of
dmp taken versus prescribed amount) between the arnlodipine (93.4 f 1.7) and
the nifedipine\felodipine (93.4 f 1.6) treatment periods (p = 0.94).
Adverse Effects:
No adverse effects were recorded by any patients during either drug
treatment period.
Table 1: Pediatric Patient Characteristics
Patient Age Gender Weight Renal hmlodipine ~ a " Channel Number (Yrs) (kg) Diagnosis Dosage Blocker
( mgUcg\dayi Therapy InitiaMau Prior to
FocaI Segmental GlomeruIos~lerosis
Autosomal Dominant Polycystic Kidncy
Disease
Cystinosis
Cystinosis
Radiation-induccd Nephri tis
Alport's Syndrome
Unknown
Bilatcral WiIm's Turnour
Adult Polycystic Kidncy Discase
Nephrotic Sy ndromc
Nitedipine PA 20 mg 0.d.
Nifedipinc XL 30 mg 0.d.
Nifedipine XL 30 mg 0.d.
Felodipinc E.R 15 mg o.d
Felodipinc E.R. 10 mg o.d.
Nifcdipinc XL 30 mg b.i.d.
Nifedipinc XL 30 mg b.i.d.
Nifedipinc XL 60 mg 0.d.
Nifcdipinc XL 30 mg 0.d.
Nifcdipinc XL
Table II: Patient Mean Home 30-dav Blood Pressure
Patient S.B.P. During S.B.P. During D.B.P. During D.B.P. During
Number NifedipineWelodipine Andodipine Nifedipine\Felodipine AmIodipine
(mm Hg) (mm Hg) (mm Hg) (mm Hg)
- -
* p-value = 0.09 (Student's paired t-test)
** p-value = 0.37 (Student's paired t-test)
DISCUSSION:
This study demonstrated that arnlodipine provides as effective monthly and
24 hour blood pressure control as that of other longacting calcium channel
blockers in pediatric renal transplant patients. These findings are supported by
adult data which demonstrated that arnlodipine is effective in treatment for
hypertension following rend t r an~~ lan t a t i on~~ .
However. amlodipine has advantages over other long-acting calcium
channel blockers which make this agent particularly suitable for the treatment of
pediatric hypertenion. First. amlodipine has a relatively long intrinsic half-life of
elirnination (36 to 48 h~urs)~%hich perrnits once-daily dosing for 24 hour blood
pressure control. Other commercially available once-daily calcium channel
blockers (e .g . nifedipine, felodipine) provide similar blood pressure control
artificially as extended-release formulations. Their long duration of action depends
on an intact delivery system of the available tablet formulations. Unfortunately.
younger children have had trouble ingesting these large tablets. Furthemore. the
dosage forms of these extended-release calcium channel blockers were designed
for adults and may be too excessive for a child's size.
Amlodipine has a unique physio-chemical structure which sets it apart from
other dihydropyridine-based calcium channel blockers. Amlodipine is water
soluble since it contains a terminal basic arnino group (pK, = 8.6) which is 94%
ionized at physiological p ~ ' 7 . Although a liquid formulation of amlodipine is not
com?iercially available. a liquid preparation of this dnig c m be readiiy created at
Our institution by dissolving a tablet dose in water using a dissolvant dose
container.
Thus, amlodipine can be administered as a liquid to children who cannot
swallow extended-release formulations of other calcium channel blockers and the
doses given can be more individualized.
Although Our study demonstrated that patient compliance during amlodipine
therapy was similar to that of other long-acting calcium channel blockers. this rnay
be an artifact since there was continuous intervention by the study investigators
throughout the study to ensure compliance. It would be expected that supenor
patient compliance with arnlodipine would be observed under normal
circumstances without such intervention. This line of reasoning is justified by the
demonstration in adults of comparitively better compliance to amlodipine therapy
38.34, compared to other long-acting calcium channel blockers .
In addition, it is not uncornmon for pediatric rend transplant patients to take
extended release formulations of long-acting calcium channel blockers more than
once-daily ( e g patient # 6. # 7, # 9, Table 1) which contrasts the situation in
amlodipine since this agent is always adrninistered once-daily. It has been
documented that cornpliance is inversely related to the number of pills taken by
patients40.
In conclusion, this study indicates that amlodipine is an effective first-line
agent for the treatrnent of hypertension following rend transplantation in pediatric
patients and this agent has advantages over other long-acting calcium channel
blockers which make it ideal for treatment of this disease in children.
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