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