Application of PK/PD in New Anti-Infective Drug Development:

Current Challenges and Future Perspectives

Seong Jang, Ph.D. Reviewer, Office of Clinical Pharmacology,

OTS/CDER/FDA

Disclaimer

The views presented here do not necessarily reflect those of the US Food and Drug Administration.

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Outline

• Summarize PK/PD principles for anti-infective drugs: Current application

• Describe potential application of PK/PD in new anti-infective drug development

• Discuss current challenges and future perspectives

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Why is PK/PD information important?

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HOST

DRUG

BUG

Drug class/MOA PK characteristics PD behavior Dose and regimen

Immunocompetence Comorbidities Previous treatment Colonization

Susceptibility Resistance mechanisms MIC

FID~ U.S. Food and Drug Administration Protecting and Promoting Public Health

www.fda.gov

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MIC T>MIC

Cmax/MIC

AUC/MIC Ratio

Time

Dru

g C

on

cen

trat

ion

Aminoglycosides Daptomycin Metronidazole Quinolones

Aminoglycosides Clindamycin Daptomycin Vancomycin Macrolides Metronidazole Linezolid Quinolones Tetracyclines

Β-Lactams Oritavancin

Cmax

Tmax

AUC

PK/PD index: Determinant of drug response

Identifying the PK/PD index that best correlates with efficacy

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•  In vitro hollow-fiber system •  Animal model of infection

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11 R2 ,. 47.5%

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24-Hour AUC/MIC Peak LeveJ/MIC Time Above MIC(%)

Determination of PK/PD Target PK/PD target: The magnitude of PK/PD index required

for desired efficacy in animal models of infection

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PK/PD target determined from animal models is used as the target for humans.

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AUC 24 /.MIC (F1r e.e. Drug) AUC 24 /MI C (Free Drug)

Current Utility of PK/PD target Dose selection for clinical studies:

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Time

200 mg • AUC24 = 15 μg·hr/mL

Target AUC24/MIC Ratio = 30

500 mg • AUC24 = 40 μg·hr/mL

100 mg • AUC24 = 8 μg·hr/mL

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nce

ntr

atio

n

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MIC = 0.5 μg/mL

Current Utility of PK/PD target: Probability of Target Attainment (PTA)

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PK/PD target & Human (Patients) PK

AUC (n=1000)   AUC/MIC (n=1000)  MIC=1   MIC=2   MIC=4   MIC=8  

10 (P1)….   10   5   2.5   1.25  

20 (P10)….   20   10   5   2.5  

30 (P25)….   30   15   7.5   3.75  

40 (P40)….   40   20   10   5  

…..   …..   ……   …….   …….  200 (P100)   200   100   50   25  

% PTA  

Target AUC24/MIC Ratio = 5 Dose: 100 mg QD

~100% 99% 90% 60%

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Probability of Target Attainment

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MIC (mg/L) 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32

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•  To determine susceptibility criteria •  To evaluate the clinical dose proposed

Potential Application of PTA as an Evidence of Drug Efficacy When a clinical efficacy trial is not feasible or is limited for infections or pathogens of low occurrence,

11 Quality of data for PK/PD target and human PK simulation are critical.

MIC (mg/L) 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32

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too rare to evaluate clinical efficacy

PTA as an Evidence of Drug Efficacy: Limitations and Challenges PK/PD target determined in animal model

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•  PD endpoints vs. Clinical Response: stasis, 1-log kill, 2-log kill, or survival in animals •  Role of immune system: Immunocompromised animals •  Concentrations in infection sites Animals ≤ Human

Q

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1 10 100 1000 AUC 24 /MIC (Free Drug)

PTA as an Evidence of Drug Efficacy: Limitations and Challenges

Human PK simulations

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•  Monte Carlo Simulation: Observed PK variability

•  Different variability b/w healthy subjects vs. patients with infection

35±8.5 (HS) vs. 33±23 (Pts)

•  Covariates of Pop. PK: Comorbidities, Infection itself, and etc

0 0

PTA as an Evidence of Drug Efficacy: Future Perspective

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•  Intensive animal studies with better animal models •  PK/PD target using clinical exposure-response data •  PK, MIC, and clinical outcomes from Phase 2 dose-ranging studies •  PK, MIC, and clinical outcomes from Phase 3 studies:

To apply to other infection sites

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Acknowledgement Kimberly Bergman, Pharm.D. Ryan Owen, Ph.D. Kellie S. Reynolds, Pharm.D. John A. Lazor, Pharm.D.

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