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Getting antifungal drug levels right – why does it matter?. David Andes University of Wisconsin. Antifungal Therapy and Aspergillus. Drugs That May Need Concentration Management Voriconazole Itraconazole Posaconazole. Antifungal Administration. Concentration matters - PowerPoint PPT Presentation
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Getting antifungal drug levels right – why does it matter?
David Andes University of Wisconsin
Antifungal Therapy and Aspergillus
Drugs That May Need Concentration Management
• Voriconazole
• Itraconazole
• Posaconazole
Antifungal Administration
• Concentration matters
• Factors that impact concentration
• Managing concentration
Fluconazole: Dose-versus-ConcentrationPredictable
Co
nce
ntr
atio
n (
AU
C)
1212
Time (hours)Time (hours)
00 11 22 33 44 55 66 77 88 99 1010 111100
10001000
20002000
30003000
40004000
50005000
60006000
70007000
80008000
Pla
sma
vo
rico
na
zole
co
nce
ntr
atio
ns
(ng
/ml)
Voriconazole: Dose-versus-ConcentrationUN-Predictable
Variable and unpredictabledose-concentration relationship for: Voriconazole,
Itraconazole, Posaconazole
Patient with Aspergillus Lung Infection
LungsAspergillus
Stomach
Liver
Patient with Aspergillus Lung InfectionTaking Antifungal Medication
Absorbing Antifungal
Absorbing Antifungal
Antifungal Working
Too Little Antifungal
Too Much Antifungal Drug
Concentration Matters
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
< 1 ug/ml > 1 ug/ml < 2 ug/ml > 2 ug/ml
% Response
% Survival
Smith et al Antimicrob Agents Chemother 2006;50:1570–1572Pascual et al Clin Infect Dis 2008;46:201
• Smith et al N = 28 patient with Aspergillosis
• Pascual et alN = 52 patients with Invasive fungal infections
Voriconazole Concentration Effect Efficacy
Voriconazole dose increased in 11 patients with concentration < 2.0, 8 of 11 survived
Toxic level
Minimumtherapeutic level
Co
nce
ntr
atio
n(a
mo
un
t o
f d
rug
)
Time
Therapeutic Window
Itraconazole concentration mg/L
Pro
ba
bility
of to
xicity
(%)
0 5 10 15 20 25
0
20
40
60
80
100
Itraconazole concentration mg/L
Pro
ba
bility
of to
xicity
(%)
Itraconazole concentration mg/L
Pro
ba
bility
of to
xicity
(%)
0 5 10 15 20 25
0
20
40
60
80
100
Tricot G et al. (1987). RID Suppl. 1, S94–S99., Boogaerts M. A. et al. (1989). Mycoses 32, Suppl. 1, 103–8., Glasmacher et al. Mycoses (1999) 42:443-9, Rex et al. (1997). CID 24:235-47, Denning, DW et al (1989) Arch Intern Med 149,2301–8., Tucker, RM et al. (1990). J Amer Acad Derm 23, 593–601, Denning, DW et al (1989). Amer J Med 86, 791–800, Lestner et al CID 2009
Pro
bab
ilit
y o
f to
xici
ty
Trough itraconazole concentrations mg/L
Itraconazole Therapeutic Window
Voriconazole Therapeutic Window
0 1 2 3 4 5 6 7 8 9 10
Voriconazole trough concentrations (mg/L)
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Pro
babi
lity
effe
ct o
r to
xici
ty
Effect Toxicity
Denning et al, CID 2002, Smith et al AAC 2006, Pascual et al CID 2008, Okuda et al Yakugaku Sasshi 2008;128:1811
Voriconazole Trough Concentration
Lik
elih
oo
d o
f S
ucc
ess
or
To
xici
ty
Posaconazole Average Concentration
0.0 0.5 1.0 1.5 2.0 2.5 3.0
% L
ikel
ihoo
d of
Suc
cess
0
20
40
60
80
100
Posaconazole Therapeutic Window
?
Walsh et al CID 2007, Krishna et al Pharmacotherapy 2009;53:958FDA. http://www.fda.gov/cder/foi/nda/2006/022003s333_NovafilTOC.htm
Factors That Impact Concentration
ABSORPTION
GI tract/Stomach
Antifungal Drug
Absorption of Antifungal Drug from Gastrointestinal Tract
Amount Absorbed
Food Effect Stomach Acid Effect
Itraconazole
(pill)
(Acid reducing drugs decrease absorption)
Itraconazole
(liquid)
Voriconazole
Posaconazole (fat best) (Acid reducing drugs decrease absorption)
Inactive Antifungal
Active Antifungal
Elimination of Antifungal Drug Via NORMAL Liver Metabolism
Inactive Antifungal
Active Antifungal
Elimination of Antifungal Drug Via SLOW Liver Metabolism
Inactive Antifungal
Active Antifungal
Elimination of Antifungal Drug Via FAST Liver Metabolism
Amount Eliminated
Liver Enzymes
(Genetics)
Other Drugs Block Enzymes
Other Drugs Enhance Enzymes
Itraconazole (pill or liquid)
++ +++
Voriconazole ++++
(major cause for variation)
++ +++
Posaconazole ++ +
Managing Concentration
When?
How Often?
Measuring Antifungal Concentration
Measuring Antifungal ConcentrationWhen and How Often?
• At the start of therapy
• After change in antifungal dose or formulation
• If the aspergillus is getting worse
• If I feel sick or have signs of antifungal toxicity
Concentration Management
• Optimize absorption
• Sometimes alter elimination
• Change the antifungal dosing regimen
• Change the antifungal
Concentration ManagementNeed to Increase Amount
Absorption Elimination Amount
Itraconazole
(pill)
• Give acidic beverage• Stop acid reducing drugs• Give with food
• Avoid inducing medications
Yes
Itraconazole
(solution)
• Avoid inducing medications
Yes
Voriconazole • Give on empty stomach • Avoid inducing drugs• Give inhibiting drug
Yes
Posaconazole • Give with fatty food • Give acidic beverage• Stop acid reducing drugs• Give more frequently
• Avoid inducing drugs Yes
Should We Measure Antifungal Concentrations?
YES
• There is significant pharmacokinetic variability among many antifungal drugs
• There are valid assays for all antifungals
• There are strong concentration toxicity and efficacy relationships for several antifungals
CONCLUSION 1
How Should We Do This?
• Measure concentration at start of therapy, with change in antifungal or with a change in how patient is doing
• If low, make sure absorption and elimination are optimized
• If still low, increase drug dose and re-measure
• If still low, consider different drug
CONCLUSION 2
Backup Slides
Itraconzole PK Variability• Coefficient of variation
– Normal volunteers (n=5) 47%– Patients (n=20) with leukemia 83-115%– Patients (n=16) 15-fold variation in concentration
• Formulation dependent (capsule > solution)• Absorption of the capsule is pH dependent, requiring an
acidic environment. Therefore, it is recommended to be given with a full meal or a cola. In contrast, absorption of the oral solution is enhanced in the fasted state
• Levels are assay dependent – Bioassay = both parent and active metabolite– HPLC = can measure both but provides parent alone
Hardin TC, et al Antimicrob Agents Chemother 1988; 32: 1310-3Lazo de la Vega S et al Drugs Under Exper Clin Res 1994; 20: 69-75Poirier JM et al. Therapie 1996; 51: 163-7., Van Peer A et al. Eur J Clin Pharmacol 1989; 36: 423-6.Jaruratanasirikul S. Eur J Clin Pharmacol 1997; 52:235-7., Van de Velde VJ et al. Pharmacotherapy 1996; 16: 424-8.Cartledge JD et al. J Clin Path 1997; 50: 477-80
• Neutropenic, itraconazole prophylaxis• Itraconazole 200 mg/d• HPLC• % with invasive fungal infection
1] Tricot G et al. (1987). Reviews of Infectious Diseases 9, Suppl. 1, S94–S99.2] Boogaerts M. A. et al. (1989). Mycoses 32, Suppl. 1, 103–8.3] Glasmacher et al. Mycoses (1999) 42:443-9
Itraconazole Concentration EffectProphylaxis
0
10
20
30
40
50
60
70
80
90
100
Patien
t Percen
t
IFI (n=20) No IFI (n=150)
Trough >0.5 ug/ml
Itraconazole Concentration EffectTreatment
• Mucosal candidiasis n=264 from 4 trials> 0.5 ug/ml 65-89% success (range dependent on MIC)< 0.5 ug/ml 44-88% success
• HIV/AIDS cryptococcal meningitis n=25HPLC assay> 1 ug/ml 100% clinical response< 1 ug/ml 66% partial response
• Coccidioidomycosis n=39Bioassay28 responders – mean peak 6.5 ± 4.211 nonresponders – mean peak 4.0 ± 3.2
• Aspergillus n=21BioassayResponders mean peak 7.5Nonresponders mean peak 4.2
Rex et al. (1997). Clin Infect Dis 24:235-47Denning, DW et al (1989) Arch Intern Med 149,2301–8.Tucker, RM et al. (1990). J Amer Acad Derm 23, 593–601Denning, DW et al (1989). Amer J Med 86, 791–800
Pharmacokinetics of Voriconazole - Influence of CYP2C19 genotype
0
1
2
3
4
5
6
7
8
Influence of CYP2C19 Genotypeon Average Steady-State Plasma
Voriconazole Concentrations
HomozygousExtensive metabolizer
(n=108)
HeterozygousExtensive metabolizer
(n=39)
HomozygousPoor
metabolizer(n=8)
Ser
um C
av
(mcg
/mL)
CYP2C19 CYP2C19
MetabolismMetabolism
% Caucasian % Caucasian
PopulationPopulation
% Asian% Asian
PopulationPopulation
PoorPoor 55 2020
HeterozygousHeterozygous 2020 4545
Extensive Extensive 7575 3535
0%
2%
4%
6%
8%
0 1 2 3 4 5 6 7 8 9 10
Voriconazole Concentration EffectToxicodynamics - Liver
Observed Weekly Occurrences Model Estimates
UPPERPREDLOWER
5/103
2/49
2/762/86
3/139
2/1774/2676/442
2/5052/600
0
2
4
6
8
0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 9+
Occ
urr
ence
(%
)
Plasma voriconazole concentration (g/ml)
Plasma voriconazole concentration category (g/ml)
Pro
ba
bil
ity
(%
)
FDA.govUeda et al Int J Hematol. 2009 Apr 2. [Epub ahead of print Matsumoto et al Int J Antimicrob Agents. 2009 Mar 2. [Epub ahead of print]
Voriconazole Concentration EffectToxicodynamics
CNS Toxicity
Pascual et al Clin Infect Dis 2008;46:201
Voriconazole Concentration EffectEfficacy
0102030405060708090
< 250 ng/mL 250-500ng/mL
> 500 or notdeterm.
Voriconazole Random Levels3 mg/kg BID
N=6 N=6 N=130
% F
ailu
res
Denning et al. Clin Infect Dis. 2002;34:563.
• Prospective, open label voriconazole for invasive aspergillosis• 142 patients• Voriconazole serum concentration monitoring in all (random)• Range < 0.1 ug/ml to 9.7 ug/ml• 4% < 0.25 ug/ml, 8% ≤ 0.5 ug/ml
0
1
2
3
4
5
6
7
8
9
Mea
n V
ori
con
azo
le T
rou
gh
C
on
cen
trat
ion
Efficacy
Yes
No
Okuda et al Yakugaku Sasshi 2008;128:1811
Voriconazole Concentration EffectEfficacy
• 21 patients•Trough concentrations ≥2• 2/3 Aspergillosis• 1/3 Febrile neutropenia• p<0.002
Posaconazole PK Variability
• 300 patients• No dosing information• No timing information
J. Wheat MiraVista Lab, personal communicationCourtney R et al. British Journal of 699 Clinical Pharmacology 2004; 57: 218-22.Gubbins PO et al. Antimicrobial Agents Chemotherapy 2006; 50: 1993-9.Ullmann AJ et al. Antimicrobial Agents Chemotherapy 2006; 50: 658-66.
Posaconazole PK Variability
Ave
rage
Con
cent
ratio
n (n
g/m
L)
0
500
1000
1500
2000
Posaconazole Pharmacokinetics in Febrile Neutropenic PatientsIndividual Average Concentrations Day 10
400 twicedaily
600 twicedaily
800 once daily
Ullmann AJ et al. Antimicrob Agents Chemother. 2006;50:658-666Kosoglou T et al J Clin Pharmacol 1990; 30:638–42.Jain R et al Clin Infect Dis 2008; 46:1627–8.Krishna et al AAC 2009;53:958
• Mechanism- at least in part due to variable absorption
• Coefficient of variation 40-80% clinical trials
• Lower concentrations in patients(52% lower) than healthy volunteers
• Increased with fractionation
• Increased with food (> fat) by3-4 X
• Significant reduction in AUC (50%)with reduced gastric acidity (PPI, etc)
• Acidic beverage increases AUC 92%
Posaconazole Concentration Effect
Walsh TJ et al. Clinical Infectious Diseases 2007; 44: 2-12.
0
10
20
30
40
50
60
70
80
Cli
nic
al R
esp
on
se (
%)
0.13 0.41 0.72 1.25
Average Plasma Concentration (mg/L)
Aspergillus and Patients (N=67)
Posaconazole Concentration Effect
• IFI Prophylaxis in GVHD– Average level in those
with IFI 0.611 ug/ml– Average level in those
without IFI 0.922 ug/ml
• FDA Guidance– Goal = average
concentration > 0.700 ug/ml
Krishna et al Pharmacotherapy 2009;53:958FDA. http://www.fda.gov/cder/foi/nda/2006/022003s333_NovafilTOC.htm
Thompson et al AAC 2009;53:2223
• 78% < 0.92 ug/ml• 66% <0.611 ug/ml• 17.3% < 0.134 ug/ml• 70% < 0.700 ug/ml
Posaconazole TDM – San Antonio, Tx
Antifungal TDM Recommendations
Andes et al AAC 2009;53:24
Recommended