Transcript A Case for Voriconazole Therapeutic Drug Monitoring to

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
Concentration (AUC)
Fluconazole: Dose-versus-Concentration
Predictable
Voriconazole: Dose-versus-Concentration
UN-Predictable
8000
Plasma voriconazole concentrations (ng/ml)
7000
Variable and unpredictable
dose-concentration
relationship for:
Voriconazole,
Itraconazole,
Posaconazole
6000
5000
4000
3000
2000
1000
0
0
1
2
3
4
5
6
7
Time (hours)
8
9
10
11 12
Patient with Aspergillus Lung Infection
Aspergillus
Lungs
Stomach
Liver
Patient with Aspergillus Lung Infection
Taking Antifungal Medication
Absorbing Antifungal
Absorbing Antifungal
Antifungal Working
Too Little Antifungal
Too Much Antifungal Drug
Concentration Matters
Voriconazole Concentration
Effect Efficacy
• Smith et al
N = 28 patient with
Aspergillosis
100%
% Response
% Survival
90%
80%
70%
• Pascual et al
N = 52 patients with
Invasive fungal
infections
60%
50%
40%
30%
20%
Voriconazole dose increased in
11 patients with concentration
< 2.0, 8 of 11 survived
10%
0%
< 1 ug/ml
> 1 ug/ml
Smith et al Antimicrob Agents Chemother 2006;50:1570–1572
Pascual et al Clin Infect Dis 2008;46:201
< 2 ug/ml
> 2 ug/ml
Concentration
(amount of drug)
Therapeutic Window
Toxic level
Minimum
therapeutic level
Time
Itraconazole Therapeutic Window
100
80
Probability of toxicity
Probability of toxicity (%)
60
40
20
0
0
5
10
15
20
25
Itraconazole concentration
mg/L
Trough itraconazole
concentrations
mg/L
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 24:23547, 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
Voriconazole Therapeutic Window
Pr obabi
ef f ect orort Toxicity
oxic it y
oflit ySuccess
Likelihood
Ef f ect
Toxic it y
1. 00
0. 90
0. 80
0. 70
0. 60
0. 50
0. 40
0. 30
0. 20
0. 10
0. 00
0
1
2
3
4
5
6
7
8
Voriconazole
Concentration
Vor ic onazole t rTrough
ough concent
r at io ns ( m g/ L)
Denning et al, CID 2002, Smith et al AAC 2006, Pascual et al
CID 2008, Okuda et al Yakugaku Sasshi 2008;128:1811
9
10
Posaconazole Therapeutic Window
% Likelihood of Success
100
?
80
60
40
20
0
0.0
0.5
1.0
1.5
2.0
2.5
Posaconazole Average Concentration
Walsh et al CID 2007, Krishna et al Pharmacotherapy 2009;53:958
FDA. http://www.fda.gov/cder/foi/nda/2006/022003s333_NovafilTOC.htm
3.0
Factors That Impact
Concentration
Absorption of Antifungal Drug
from Gastrointestinal Tract
GI tract/Stomach
Antifungal Drug
ABSORPTION
Amount Absorbed
Food Effect
Stomach Acid
Effect
Itraconazole
(pill)

Itraconazole
(liquid)

 (Acid reducing
drugs decrease
absorption)

Voriconazole


Posaconazole
 (fat best)
 (Acid reducing
drugs decrease
absorption)
Elimination of Antifungal Drug
Via NORMAL Liver Metabolism
Active Antifungal
Inactive Antifungal
Elimination of Antifungal Drug
Via SLOW Liver Metabolism
Active Antifungal
Inactive Antifungal
Elimination of Antifungal Drug
Via FAST Liver Metabolism
Active Antifungal
Inactive Antifungal
Amount Eliminated
Liver Enzymes
(Genetics)
Itraconazole
(pill or liquid)
Voriconazole
Posaconazole
++++
(major cause for
variation)
Other Drugs
Block Enzymes
Other Drugs
Enhance
Enzymes
++
+++
++
+++
++
+
Managing Concentration
Measuring Antifungal Concentration
When?
How Often?
Measuring Antifungal Concentration
When 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 Management
Need to Increase Amount
Itraconazole
(pill)
Absorption
Elimination
Amount
• Give acidic beverage
• Stop acid reducing drugs
• Give with food
• Avoid inducing
medications
Yes
• Avoid inducing
medications
Yes
Itraconazole
(solution)
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
CONCLUSION 1
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 2
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 remeasure
• If still low, consider different drug
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: 1310-3
Lazo de la Vega S et al Drugs Under Exper Clin Res 1994; 20: 69-75
Poirier 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
Itraconazole Concentration Effect
Prophylaxis
70
60
Study 1
Study 2
• Neutropenic, itraconazole
prophylaxis
• Itraconazole 200 mg/d
• HPLC
• % with invasive fungal
infection
% IFI
50
40
30
20
10
0
< 0.25 ug/ml
Patient Percent
100
90
80
70
60
50
40
30
20
10
0
> 0.25 ug/ml
Trough >0.5 ug/ml
IFI (n=20)
No IFI (n=150)
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 Effect
Treatment
• 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=25
HPLC assay
> 1 ug/ml 100% clinical response
< 1 ug/ml 66% partial response
• Coccidioidomycosis n=39
Bioassay
28 responders – mean peak 6.5 ± 4.2
11 nonresponders – mean peak 4.0 ± 3.2
• Aspergillus n=21
Bioassay
Responders mean peak 7.5
Nonresponders mean peak 4.2
Rex et al. (1997). Clin Infect Dis 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
Pharmacokinetics of Voriconazole Influence of CYP2C19 genotype
Influence of CYP2C19 Genotype
on Average Steady-State Plasma
Voriconazole Concentrations
Serum Cav (mcg/mL)
8
7
6
5
4
3
2
1
0
Homozygous
Extensive metabolizer
(n=108)
CYP2C19
Metabolism
Poor
Heterozygous
Extensive metabolizer
(n=39)
% Caucasian
Population
Homozygous
Poor
metabolizer
(n=8)
% Asian
Population
5
20
Heterozygous
20
45
Extensive
75
35
Voriconazole Concentration Effect
Toxicodynamics - Liver
Observed Weekly Occurrences
Model Estimates
8%
8
Occurrence (%)
6
5/103
2/49
4
2/76
3/139
2
6/442 4/267
2/600
2/86
Probability (%)
UPPER
PRED
LOWER
6%
4%
2%
2/177
2/505
0
0%
0-1
1-2
2-3
3-4
4-5
5-6
6-7
7-8
8-9
Plasma voriconazole
concentration category (g/ml)
9+
0
1
2
FDA.gov
Ueda 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]
3
4
5
6
7
8
Plasma voriconazole
concentration (g/ml)
9
10
Voriconazole Concentration Effect
Toxicodynamics
CNS Toxicity
Pascual et al Clin Infect Dis 2008;46:201
Voriconazole Concentration Effect
Efficacy
•
•
•
•
•
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
% Failures
Voriconazole Random Levels
3 mg/kg BID
90
80
70
60
50
40
30
20
10
0
< 250 ng/mL
Denning et al. Clin Infect Dis. 2002;34:563.
N=6
250-500
ng/mL
> 500 or not
determ.
N=6
N=130
Voriconazole Concentration Effect
Efficacy
9
Mean Voriconazole Trough
Concentration
8
7
Yes
No
6
5
4
3
2
1
0
Efficacy
Okuda et al Yakugaku Sasshi 2008;128:1811
• 21 patients
•Trough concentrations ≥2
• 2/3 Aspergillosis
• 1/3 Febrile neutropenia
• p<0.002
Posaconazole PK Variability
50
45
Patient %
40
• 300 patients
• No dosing information
• No timing information
35
Patient %
30
25
20
15
10
5
0
ND
<0.5
<1
>1
>2
J. Wheat MiraVista Lab, personal communication
Courtney 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
• Mechanism- at least in part
due to variable absorption
• Lower concentrations in patients
(52% lower) than healthy volunteers
• Increased with fractionation
• Increased with food (> fat) by
3-4 X
• Significant reduction in AUC (50%)
with reduced gastric acidity (PPI, etc)
• Acidic beverage increases AUC 92%
Ullmann AJ et al. Antimicrob Agents Chemother. 2006;50:658-666
Kosoglou 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
Average Concentration (ng/mL)
• Coefficient of variation 40-80%
clinical trials
Posaconazole
Pharmacokinetics in Febrile
Neutropenic Patients
Individual Average
Concentrations Day 10
400 twice
daily
600 twice
daily
800 once
daily
Posaconazole Concentration Effect
Clinical Response (%)
80
Aspergillus and Patients (N=67)
70
60
50
40
30
20
10
0
0.13
0.41
0.72
Average Plasma Concentration (mg/L)
Walsh TJ et al. Clinical Infectious Diseases 2007; 44: 2-12.
1.25
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;53:958
FDA. http://www.fda.gov/cder/foi/nda/2006/022003s333_NovafilTOC.htm
Posaconazole TDM – San Antonio, Tx
• 78% < 0.92 ug/ml
• 66% <0.611 ug/ml
• 17.3% < 0.134 ug/ml
• 70% < 0.700 ug/ml
Thompson et al AAC 2009;53:2223
Antifungal TDM Recommendations
Andes et al AAC 2009;53:24