Dosing Regimen Individualization

Dosing Regimen Individualization

Age

Subcategories

Newborn 1-7 d

Neonate 8 d – 2 mo

Infant 2 mo – 1 yr

Child 1 – 12 yr

Adolescent 12 – 20 yr

Adult 20 – 70 yr

Elder > 70 yr

Age of usual adult for whom the “usual adult regimen” is prescribed is 55 years.

Confounding variables

Influence of age on pharmacokinetics is difficult to separate from the influence of body weight in the young, and from disease in adults.

Cross-sectional vs. Longitudinal Study Designs

Cross-sectional design: group subjects by age and compare PK parameter values in the different age groups:

Age CL

10-20 aaa.a

21-30 bbb.b

31-40 ccc.c

Longitudinal design: Repeatedly measure PK value in the same subjects over a long period of time.

Pitfall with cross-sectional design

An apparent age-associated effect may be due to differences in longevity that also influence the PK parameter.

Example: Effect of age on eye color. Assume the people with blue eyes also have a relatively short life span, but this is unknown at the time of the study.A cross-sectional study would indicate that the fraction of people with blue eyes declined with increasing age.

A longitudinal study would show the truth, that people with blue eyes did not live as long.

Conclusion: eye color changes with increasing age.

V and age: protein bindingfup tends to be elevated in newborns and in the elderly.

V values tend to be elevated for protein-bound drugs.

Grandison and Boudinot. Age-related changes in protein binding of drugs. Clin. Pharamacok. 38:271-290,2000.

Review of literature for fup values measured in young and elderly subjects/patients found 106 studies for 66 drugs.

28/106 studies showed fup elevated in the elderly

7/106 studies showed fup decreased in the elderly

71/106 studies showed no change for fup in the elderlyAge-related changes [in adults] are usually not

clinically important – Grandison and Boudinot.

, male; o, female.

B.

Th.

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Plasma Proteins

V and age: protein binding

Age NKd

[mg/L]

n[P][mg/L]

fup

1 – 8 d 15 26.9 135 0.30

7 – 15 m 4 0.16

2 – 6 yr 5 0.16

22-25 yr 8 14.1 327 0.058

40 – 49 yr

4 15.4 279 0.076

81 – 88 yr

3 16.4 217 0.113

Hayton and Stoeckel. Age associated changes in ceftriaxone pharmacokinetics. Clin. Pharamacok. 11:76-86,1986.

Ceftriaxone

Adiposity: increases as adults age

~20% Body Weight in young adultsAge and Gender Dependent: Children age 15 yr and below

BF% = 1.51BMI – 0.70age –3.6Gen + 1.4 AdultsBF% = 1.2BMI + 0.23age –10.8Gen - 5.4

BMI = body mass index = BW/H2 (kg/m2)

V and age: ceftriaxone

Age NV

[L/kg]

V

[L/m2]

1 – 8 d 24 0.504 6.57

9 – 30 d 10 0.650 9.21

1 – 12 m 11 0.538 9.64

1 – 6 yr 8 0.339 8.53

18 – 49 yr 50 0.157 6.03

50 – 74 yr 9 0.151 5.79

75 – 92 yr 11 0.146 5.16

Obesity and V Values

Drug log P control obese control obesesotalol -1.5 70.8 81 1.1 0.9caffeine -0.16 40.1 48.3 0.59 0.44bisoprolol -0.02 146 173 2.9 1.9cyclophosphamide 0.63 34.5 37.1labetalol 1.09 279 368 4.8 3.8propranolol 1.29 180 226.8 3.1 2.4glipizide 1.91 17.2 19.5 0.21 0.2nebivolol 2.39 673 898 11.2 9.4carbamazepine 2.45 69.7 98.4 0.96 0.87phenytoin 2.47 40.2 82.2 0.61 0.68glibenclamide 3.08 56.8 47 0.81 0.44sufentanil 3.24 346 547 4.8 5.8

V [L] V [L/kg]

log P = log [octanol / pH 7.4 buffer] partition coefficient

log V vs. log Plog V control

1.000

1.200

1.400

1.600

1.800

2.000

2.200

2.400

2.600

2.800

3.000

-2 -1 0 1 2 3 4

log P

log

V

-Blockers and Obesity: V

log V = 0.23(0.04)log D + 2.1(0.07)

log V = 0.25(0.05)log D + 2.2(0.07)

control obese

G. Cheymol. Effects of obesity on pharmacokinetics. Clinical Pharmacokinetics 39:215-231,2000.

Obesity and V

General lack of correlation between V and log P is attributed in part to variability in the affinity of drug for lean tissue.

•affinity for lean tissue is unrelated to log P and highly variable among drugs.

•amine functional group seems to increase affinity for lean tissue.

The difference between actual and ideal body weight in obesity is not all adipose tissue; 20-40% of the additional weight is lean.

CL and age: CLR

11,347 CLCR values from 5,146 subjects

Hallynck T, Soep H, Thomis J, Boelaert J, Daneels R, Dettli L: Should Clearance be Normalised to Body Surface or to Lean Body Mass? Br. J. Pharmac. 11:523-526, 1981.

CLCR = [140 – age] W / 70

CLCR – longitudinal study, adults

Lindem

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Am

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Soc.

3

3:2

78

,19

85

.

Baltimore longitudinal study of aging.

254 normal subjects; not taking diuretics or antihypertensives, and no renal or urinary tract disease.

One-third had no decrease in renal function over time.

CL and age: CLH

Rowland and Tozer. Fig. 15.9, p. 239.

n = 307

oxidative metabolism

- 1% / yr

CLR and age: children

Hayton, Stoeckel, et al. Antimicrob. Agents Chemother. 35:720-725, 1991; 40:567-574, 1996.

cefetamet

b = 0.661

CLR cefetamet: age-weight model

age

CL

R

CLR,im

CLR,m

a

agekmaR

agekimRR

matmat eCLeCLageCL 1,,

Age-Weight Model agek

maRagek

imRRmatmat eCLeCLageCL 1,,

bimR aWCL ,

bmaR cWCL ,

agekbagekbR

matmat ecWeaWweightageCL 1,

The least-squares fit of this equation to cefetamet CL values in children is indicated by the solid circles.

GFR: maturation and growth

1

10

100

1 10 100

Weight, kg

GF

, mL

/min

63 healthy children

age 2 d to 12 yr

agekbagekb matmat ecWeaWweightageGFR 1,

a[mL/min]

2.60

b 0.662

c[mL/min]

8.14

kmat

mo-10.0882

(t1/2)mat

mo7.9


From the maturation half life, children age 2 yr and older have fully mature renal function. DR need be adjusted only for body weight.

The body weight adjustment should use the b value of 0.662; i.e., a body surface area adjustment is appropriate.

7.0

,2

2

,, 7087.1

kgkgW

Dm

mBSADD adultM

childadultMchildM


For children less than 2 yr of age, adjustment of the adult dosage must include adjustment for immaturity as well as for body size.

ageage eWeWWageGFR 0882.0662.00882.0662.0 114.860.2,

1. Divide through by W; this results in CLR per kg W.2. Divide through by 1.43 mL min-1 kg-1 (adult GFR of 100 mL/min per 70 kg). This results in the fraction of the adult normal GFR for a child of weight W and age in months.

ageGFR eWFRAC 0882.0338.0 87.369.5


ageGFR eWFRAC 0882.0338.0 87.369.5

For a child less than 2 yr and a drug cleared primarily by the kidneys, 1) calculate FRACGFR:

2) Calculate the dosing rate as a fraction of the adult dosing rate:

GFRadultchild FRACkgmgDRkgmgDR //

Example

The usual adult dosage for this antibiotic is 250 mg t.i.d. What should the regimen be for a 4 mo. old, 12 lb infant?

FRACGFR = 5.44-0.338(5.69 – 3.87e-0.0882(4)) = 1.68

DM,infant = DM,adult x FRACGFR

= (250 mg / 70 kg)(1.68) = 6.00 mg/kg

DM,infant = 6.00 mg/kg x 5.44 kg = 32.6 mg t.i.d.

Features of the age,weight model

1. Degree of maturation is indicated by the ratio of c / a

8.14 / 2.60 = 3.12. The time for maturation was characterized by the maturation half life; 3.3 t1/2,mat was about 2 yr.

3. The body weight exponent was 0.662, which suggests that BSA is the appropriate index for adjustment of the adult DR for children 2 yr of age and older.

Features, cont.

4. GFR per kg body weight is influenced positively by maturation and negatively by growth, over two time frames.

1.0

1.5

2.0

2.5

3.0

3.5

0 50 100 150

Age, months

GF

R, m

L/m

in/k

g

usual adult value

GFR from birth to 100 yr

GFR = (140 - age) W / 70

GFR (mL/min) = 2.60W0.662e-0.0882age + 8.14W0.662(1 - e-0.0882age) – (age/12)(W/70)0.662

age, mo.; W, kg

0

20

40

60

80

100

120

140

0 1 2 3 4 5 6 7 8 9 10 11

age [mo**.33]

GF

R [

mL

/min

]

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

GF

R [

mL

/min

/kg

]

CLH and age: children

S.N. de Wildt, et al., Cytochrome P450 3A ontogeny amd drug disposition. Clin. Pharmacok. 37:485-505,1999.

S.N. de Wildt, et al., Cytochrome P450 3A ontogeny amd drug disposition. Clin. Pharmacok. 37:485-505,1999.

Liver Volume and Drug CL vs. Age in Children

Murry, Crom, … Evans. Drug Metab. Disp. 23:1110-1116, 1995

8 boys/8 girls median range

Age [yr] 9.7 3.3-18.8

Weight [kg] 40.8 11.9-88.5

BSA [m2] 1.37 0.57-2.0

Liver Vol. [mL]

973 469-1640

lorazepam eliminated primarily by glucuronidation

p > 0.05

p > 0.05


antipyrine eliminated primarily by CYP450-mediated oxidation

p > 0.05

p < 0.05



Indocyanine Green clearance. CL is by the liver and E 1. CLICG is widely used as a measure of hepatic blood flow.

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Dosing Regimen Individualization