Pk/Pd of antifungal drugs

Johan W. Mouton MD PhD FIDSA Professor pharmacokinetics and pharmacodynamics 

JWM New Delhi 19-03-2015

Disclosures

Research grants – advisory boards – speaker JWM New Delhi 19-03-2015

therapeutic success

Dosing should be such that the level of antmicrobial activity is associated with a high likelihood of therapeutic success.

DOSE

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Efficacy of the drug

Exposure to the bug In vivo (PK)

Potency of a drug (MIC)

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Potency of a drug in vitro (MIC)

Exposure to the bug in vivo (PK)

Dosing Regimen

Antimicrobial Efficacy of the Drug  (Microbiological Cure)

Effect on Host  ( Clinical Cure)

Mouton et al., Drug Resistance Updates 2011

ACTVITY in vitro (MIC)

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CONCENTRATIONS in vivo (PK)

DOSING regimen

ANTMICROBIAL EFFICACY  (Microbiological Cure) Other factors

CLINICAL EFFICACY (Clinical Cure) Mouton et al., Drug Resistance Updates 2011

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Probability of cure after treatment with fluconazole Oropharyngeal Candidiasis n=132 Culture-results with MIC-values

Treatment with fluconazol Doses 50 – 800 mg

Individual Dose

MIC-values per individual

Determine Dose/MIC for each patient

Microbiological outcome (candida cured) Clinical outcome JWM New Delhi 19-03-2015

Probability of cure after treatment with fluconazole Oropharygeal Candidiasis n=132

1.0

•Prob cure correlates with EC50

prob cure

0.8

R²

43.69

Dose/MIC

0.9938

0.6

•POSITIVE correlation with 0.4

Dose

0.2

•INVERSE correlation with MIC

0.0 1

10

100

1000

Dose/MIC

Each data point represents the proportion of patients cured within a group representing a certain Dose/MIC value Rodriguez- Tudela et al, AAC 2007

JWM New Delhi 19-03-2015

Probability of cure after treatment with fluconazole Oropharygeal Candidiasis  n=132

Pharmacodynamic Target

1.0 EC50

prob cure

0.8

R²

43.69 0.9938

0.6 0.4 0.2 0.0 1

10

100

1000

Dose/MIC

NOTE : MICs by EUCAST method Rodriguez‐ Tudela et al, AAC 2007

JWM New Delhi 19-03-2015

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Probability of cure after treatment with fluconazole Oropharygeal Candidiasis  n=132

Pharmacodynamic Target

1.0 EC50

prob cure

0.8

R²

43.69 0.9938

Uncertainty

0.6 0.4 0.2 0.0 1

10

100

1000

Dose/MIC

NOTE : MICs by EUCAST method Rodriguez‐ Tudela et al, AAC 2007

JWM New Delhi 19-03-2015

Probability of cure after treatment with fluconazole Oropharygeal Candidiasis n=132

1.0

•Prob cure correlates with EC50

prob cure

0.8

R²

43.69

Dose/MIC

0.9938

0.6

•POSITIVE correlation with

0.4

Dose

0.2

•INVERSE correlation with MIC

0.0 1

10

100

1000

Dose/MIC

Each data point represents the proportion of patients cured within a group representing a certain Dose/MIC value Rodriguez- Tudela et al, AAC 2007

JWM New Delhi 19-03-2015

Probability of cure after treatment with fluconazole Oropharygeal Candidiasis  n=132 IF MIC = 4 mg/L WHAT IS THE LOWEST DOSE YOU ARE COMFORTABLE WITH? Pharmacodynamic Target 1.0 EC50

prob cure

0.8

R²

Dose

43.69 0.9938

0.6 0.4 0.2 0.0 1

10

100

1000

1. 200 mg 2. 400 mg 3. 800 mg 4. 1600 mg

Dose/MIC

Rodriguez- Tudela et al, AAC 2007

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Probability of cure after treatment with fluconazole Oropharygeal Candidiasis  n=132 IF Dose = 400 mg WHICH MIC ARE YOU COMFORTABLE WITH?

Pharmacodynamic Target

1.0 EC50

prob cure

0.8

R²

43.69 0.9938

0.6

1. 1 mg/L 2. 2 mg/L 3. 4 mg/L 4. 8 mg/L

0.4 0.2 0.0 1

10

100

1000

Dose/MIC Rodriguez- Tudela et al, AAC 2007

JWM New Delhi 19-03-2015

Probability of cure after treatment with fluconazole Oropharygeal Candidiasis  n=132

1.0 EC50

prob cure

0.8

R²

•If The standard dose is 400 mg

43.69 0.9938

0.6

•It follows that the breakpoint is 400/100 = 4 mg/L

0.4 0.2 0.0 1

10

100

1000

Dose/MIC

Rodriguez- Tudela et al, AAC 2007

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Susceptible (S) A micro-organism is defined as susceptible by a level of antmicrobial activity associated with a high likelihood of therapeutic success. A micro-organism is categorized as susceptible by applying the appropriate breakpoint in a defined phenotypic test system. Note: This breakpoint may be altered with legitimate changes in circumstances Intermediate (I) A micro-organism is defined as intermediate by a level of antimicrobial activity associated with indetermiate therapeutic effect. A micro-organism is categorized as intermediate by applying the appropriate breakpoints in a defined phenotypic test system. Note: This breakpoints may be altered with legitimate changes in circumstances. Resistant (R) bacteria are defined as resistant by a level of antimicrobial activity associated with a high likelihood of therapeutic failure. A micro-organism is categorized as resistant by applying the appropriate breakpoint in a defined phenotypic test system. Note: This breakpoint may be altered with legitimate changes in circumstances

WWW.EUCAST.ORG

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% successful treatment

Fluconazole , candidiasis

100 80 60 R²

0.9655

EC50

40

36.50

20 0 0

1

2

3

log dose/mic

Mouton, PK/PD of Azoles, 2007

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Problem (or is it?): What if the standard dose is different? What if the population is different?

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ACTVITY in vitro (MIC)

CONCENTRATIONS in vivo (PK)

DOSING regimen

ANTMICROBIAL EFFICACY  (Microbiological Cure) Other factors

CLINICAL EFFICACY (Clinical Cure) Mouton et al., Drug Resistance Updates 2011

JWM New Delhi 19-03-2015

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ACTVITY in vitro (MIC)

CONCENTRATIONS in vivo (PK)

DOSING regimen

ANTMICROBIAL EFFICACY  (Microbiological Cure) Other factors

CLINICAL EFFICACY (Clinical Cure) Mouton et al., Drug Resistance Updates 2011

ACTVITY in vitro (MIC)

JWM New Delhi 19-03-2015

CONCENTRATIONS in vivo (PK)

DOSING regimen

ANTMICROBIAL EFFICACY  (Microbiological Cure) Other factors

CLINICAL EFFICACY (Clinical Cure) Mouton et al., Drug Resistance Updates 2011

JWM New Delhi 19-03-2015

Pharmacokinetic parameters : Measures of Exposure AUC is usually linearly related to Dose

AUC

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Pharmacokinetic parameters : Measures of Exposure AUC is usually linearly related to Dose Dose x 2 = AUC x 2 Dose x 4 = AUC x 4

AUC

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So what determines the relationship between dose and exposure?

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Fluconazole Dose - AUC Relationship

Rodriguez-Tudela et al, AAC 2007

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Relationship Dose – Exposure - MIC volunteer data 400 mg/dose 1000

AUC/MIC

Average 100

10

1

2

4

8

16

32

MIC mg/L

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So what more determines the relationship between dose and exposure?

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Pharmacokinetics

• Some patients are more equal than others

Oktoberfest

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auc distribution fluconazole monte carlo simulation

rel freq

0.2

0.1

0 40 .000 8 .00 12 0.000 160.00 0 200.000 240.000 280.000 320.000 360.000 400.000 440.000 480.000 520.000 560.000 600.000 640.000 680.000 720.000 760.000 800.000 0. 0 00 0

0.0

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Exposure by MIC of fluconazole

volunteer data 400 mg/dose 1000

AUC/MIC

Average 100

10

1

2

4

8

16

32

MIC mg/L

Eucast rationale document, 2007

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Exposure by MIC of fluconazole Monte Carlo Simulations

volunteer data 400 mg/dose 1000

AUC/MIC

Average 100

10

1

2

4

8

16

32

MIC mg/L

Eucast rationale document, 2007

JWM New Delhi 19-03-2015

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Exposure by MIC of fluconazole Monte Carlo Simulations

volunteer data 400 mg/dose 1000

AUC/MIC

Average 100

10

1

2

4

8

16

32

MIC mg/L

Eucast rationale document, 2007

JWM New Delhi 19-03-2015

Exposure by MIC of fluconazole Monte Carlo Simulations

volunteer data 400 mg/dose 1000

AUC/MIC

Average 100

10

1

2

4

8

16

32

MIC mg/L

Eucast rationale document, 2007

JWM New Delhi 19-03-2015

Exposure by MIC of fluconazole Monte Carlo Simulations

volunteer data 400 mg/dose 1000

AUC/MIC

Average 95% CI 99% CI

100

10

1

2

4

8

16

32

MIC mg/L

Target AUC/MIC ratio = 50 Target Dose/MIC ratio = 100 Eucast rationale document, 2007

JWM New Delhi 19-03-2015

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Susceptible (S) A micro-organism is defined as susceptible by a level of antmicrobial activity associated with a high likelihood of therapeutic success. A micro-organism is categorized as susceptible by applying the appropriate breakpoint in a defined phenotypic test system. Note: This breakpoint may be altered with legitimate changes in circumstances Intermediate (I) A micro-organism is defined as intermediate by a level of antimicrobial activity associated with indetermiate therapeutic effect. A micro-organism is categorized as intermediate by applying the appropriate breakpoints in a defined phenotypic test system. Note: This breakpoints may be altered with legitimate changes in circumstances. Resistant (R) bacteria are defined as resistant by a level of antimicrobial activity associated with a high likelihood of therapeutic failure. A micro-organism is categorized as resistant by applying the appropriate breakpoint in a defined phenotypic test system. Note: This breakpoint may be altered with legitimate changes in circumstances

WWW.EUCAST.ORG

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Susceptibility Report LAB REPORT •

Provides Clinician/Consultant guidelines how to optimally treat a patient (Freely translated from EUCAST guideline)

BASED ON EXPOSURES OF COMMON DOSES

JWM New Delhi 19-03-2015

Susceptibility Report LAB REPORT •

Provides Clinician/Consultant guidelines how to optimally treat a patient (Freely translated from EUCAST guideline)

BASED ON EXPOSURES OF COMMON DOSES IN ADULTS JWM New Delhi 19-03-2015

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Exposures in children : differences

• Lower EXPOSURE then expected •Clearance in individual

1.0 EC50

prob cure

0.8

R²

43.69 0.9938

0.6 0.4 0.2 0.0 1

10

100

1000

Dose/MIC

JWM New Delhi 19-03-2015

Pharmacokinetic parameters of Fluconazole by age group 100

3.0

t 1/2

2.5 2.0

60 1.5 40

Vd (l/kg)

t 1/2 (h)

80

Vd

1.0

ad ul ts

ye ar 12 s -1 6 ye ar s

ye ar s

212

0. 25 -2

2

1

1

w ee k

0.0

w ee ks

0.5

0

da y

20

age group Mouton, Antimicrob Pharmacodynamics in Theory and Clin Practice 2007, 357 JWM New Delhi 19-03-2015

AUC per unit dose (mg/kg) of fluconazole differences by age group

AUC

200

100

w ee 0. ks 25 -2 ye ar 2s 12 ye ar 12 s -1 6 ye ar s ad ul ts

2

w 1

1

da y

ee k

0

age group

Mouton, Antimicrob Pharmacodynamics in Theory and Clin Practice 2007, 357 JWM New Delhi 19-03-2015

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auc distribution fluconazole monte carlo simulation 0.2

rel freq

0.5-2 yr

0.1

0 40.000 8 .00 120.000 160.000 200.000 240.000 280.0 0 0 320.000 360.000 0 40 .000 440.000 480.000 520.000 560.000 600.000 640.000 680.000 720.0 0 0 760.000 800.000 0. 0 00 0

0.0

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AUC per unit dose (mg/kg) of fluconazole

AUC

200

100

da y 1

1

w ee k 2 w ee 0. ks 25 -2 ye ar 2s 12 ye ar 12 s -1 6 ye ar s ad ul ts

0

age group Mouton, Antimicrob Pharmacodynamics in Theory and Clin Practice 2007, 357 JWM New Delhi 19-03-2015

MCS of fluconazole: variability in children children data 10 mg/kg 1000

AUC/MIC

Average 95% CI 99% CI

100

10

1

2

4

8

16

32

MIC mg/L

400 mg dose in adults compares to ~ 20 mg/kg JWM New Delhi 19-03-2015

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Exposures in children: • Generally lower – increase dose • Larger variability – be aware, possible increase dose or monitor or estimate clearance • These insights can help to rationalize dosing regimens in children

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To summarize:

• There is a good relationship for exposure and response • This translates to dosing regimens for the general population • Breakpoints are based on the most common lowest dose • Other populations may require doseadjustments • For non-predictable concentrations: TDM is a requirement

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