Phase I Issues for Novel TB Drugs

Dakshina M. Chilukuri, Ph.D.Office of Clinical Pharmacology and Biopharmaceutics, FDA

OPEN FORUM ON KEY ISSUES IN TB DRUG DEVELOPMENT

December 6-7, 2005

Disclaimer

• The opinions expressed during this presentation are those of the speaker, and do not necessarily represent those of the Food and Drug Administration.

Outline• TB Drug Development

• Clinical Pharmacology Assessments– Studies to characterize clinical pharmacology

• In Vitro studies • In Vivo studies

– Evaluation of Exposure-Response Relationships

• Summary

Desired Attributes of a Novel TB Drug

• Improved pharmacokinetic (PK) properties to reduce number of doses and duration of treatment

• Improved treatment of MDR-TB

• Compatible with AIDS treatment regimens

• More effective against latent TB infection

• Inexpensive

Clinical Pharmacology Information

• PK characterization– Single dose in healthy subjects– Multiple/steady-state dosing in healthy subjects

and patients

• Mass balance/radiolabeled ADME study

• Characterization of metabolism in vitro using human liver preparations– Evaluate potential of TB drug as a substrate and to

act as an inhibitor and/or inducer of CYP450 enzymes

Clinical Pharmacology Information (cont.)

• Influence of intrinsic factors on drug PK:

– Age, race, gender, renal impairment and/or hepatic impairment

• Influence of extrinsic factors on drug PK:

– Drug interaction studies

• Special studies:

– Evaluation of exposure-response relationships

– Assessment of QT prolongation

Biopharmaceutics information

• Food effect study

• Pivotal bioequivalence (BE) study that links ‘clinical trial formulation’ and ‘to-be marketed formulation’

• In vitro dissolution

• Evaluation of other formulation effects

Drug Interaction Studies

• Results from mass balance/radiolabeled ADME study and in vitro metabolism profiling are important in determining the need for additional in vivo drug interaction studies

Drug Interaction Studies (cont.)

• Evaluate potential of the TB drug to interact with the major CYP450 enzymes:

• CYP1A2• CYP2C8• CYP2C9• CYP2C19• CYP2D6• CYP3A4/5

An approach to study CYP-Based Drug-Drug Interaction Studies

Yes No Yes No

Yes No

In Vitro metabolism InformationCYP 1A2, 2C8, 2C9, 2C19, 2D6, 3A

<Studies in human tissues>

NME not a substrate or NME a substrate but

contribution of pathway not major

Label as such based on in vitro and in vivo

disposition data

NME is a substrate and contribution of pathway to elimination major or

unclear

Conduct in vivo studies with most potent

inhibitor(s)/inducer(s)

Presence of significant

interaction?

Dosage Adjustment

needed?

No further studies needed

General Label based on in vitro and in vivo data

NME is an inducer or inhibitor or no in

vitro data

Study other inhibitors/inducers selected based on

likely co-administration

Conduct in vivo studies with most sensitive/specific

substrate(s)

Study other substrates selected based on likely co-administration narrow

therapeutic range

No further studies needed

general label based on in vitro and in

vivo data

NME not an inducer or inhibitor

Label as such based on in vitro

data

Dosage Adjustment

needed?

Yes No

Presence of significant

interaction?

Drug Interaction Studies (cont.)

Drug Metabolism Excretion Known drug interactions

Isoniazid Acetylation 75-95% in urine Drugs metabolized by CYP1A2, 2C9, 2C19, 2A6 and 3A

Pyrazinamide Predominantly hydrolyzed to 5-OH-pyrazinoic acid

3% in urine No known interactions with drugs metabolized by the CYP enzyme system

Ethambutol 8-15% metabolized by liver

75% in urine No known CYP450 interactions

Rifampin Metabolized to 25-desacetyl-rifampin

30% in urine Potent CYP450 inducer (variety of drugs)

Currently marketed TB drugs

Drug Interaction Studies (cont.)Study Design Considerations

• Overall Objective: Determine plasma exposure of TB drug in absence and presence of interacting drug(s)

• Appropriate design depends on several factors:– PK characteristics of TB drug and its metabolites – Safety margin of TB drug– Nature and characterization of the suspected

interaction for TB drug• Selection of Interacting drug(s)

– Known CYP450 substrate/inhibitor/inducer– Clinical relevance

Drug Interaction Studies (cont.)Study Design Considerations

• Methodology– Number of subjects/patients– Dosage regimen

• Single vs. multiple dose• Clinically relevant for both TB drug and

interacting drug

– PK Sampling schemes• Traditional • Sparse for population PK analyses/screen

Drug Interaction Studies (cont.)Study Design Considerations

• End Points– PK parameters for systemic exposure (AUC, Cmax,

Tmax) and disposition (CL, Vd, T½)

– PD/response measures (efficacy/safety) can provide additional information

• Data Analysis and Interpretation of Results– Results should be reported as 90% confidence

intervals (CI) about the geometric mean ratio of the observed PK parameters (AUC, Cmax) in presence and absence of interacting drug

Exposure-Response Studies

• FDA Guidance for Industry: Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory Applications

• Objective: explore relationship of drug exposure to response (e.g., biomarkers, potentially valid surrogate endpoints, clinical effects, adverse events) in order to – link preclinical with clinical findings – provide evidence that the hypothesized mechanism of

action is affected by the drug (proof of concept) – provide evidence that the effect of the drug leads to

desired clinical outcome – provide guidance for determining an optimal dosage

regimen

Opportunities for Exposure-Response Analyses in TB Drug Development

• Limited understanding of the PK/PD relationships for TB drugs:– Wide acceptance of current short-course

regimens– Limited number of new drug candidates

developed in the last two decades– Slow growth of Mycobacterium tuberculosis – Latency of the TB infection

Opportunities for Exposure-Response Analyses in TB Drug Development

• Typical PK/PD indices for anti-infective drugs that may be useful for TB drugs:– AUC/MIC (Rifampin)

– Cmax/MIC (Isoniazid)

– Time above MIC– Are there others for TB

drugs?

1: Bull World Health Organ 23:535– 585

2 : Antimicrob Agents Chemother 47:2118–2124, 2003

3: Am J Respir Crit Care Med Vol 172. pp 128–135, 2005

Drug PK/PD parameter

Isoniazid Cmax/MIC1

Rifampin AUC/MIC2,3

Rifapentine Unknown

Pyrazinamide Unknown

Opportunities for Exposure-Response Analyses in TB Drug Development

• Sponsors are encouraged to explore potential exposure-response relationships during TB drug development

• Obtaining such exposure-response information in Early Bactericidal Activity (EBA) studies and other phases of TB drug development may enable rational selection of an appropriate TB dosage regimen(s) to use in pivotal trials

21

Summary

Phase I Studies

Phase II Studies

Phase III Studies

Approval

•Clinical Pharmacology

• Dose ranging• Exposure-response

• Optimal dose selection

• Safety & Efficacy•Exposure-response •Population Pharmacokinetics

21

Summary

Phase I Studies

Phase II Studies

Phase III Studies

Approval

•Clinical Pharmacology

• Dose ranging• Exposure-response

• Optimal dose selection

• Safety & Efficacy• Exposure-response • Population

Pharmacokinetics

Right drug?

Clinical Pharmacology & Biopharmaceutics

Right patient?

Right dose/dosage regimen?

Questions???

Backup slides

PK/PD of INH, Rifampin and Pyrazinamide

Eur J Clin Microbiol Infect Dis (2004) 23: 243–255

PK/PD of Fluoroquionolones

Eur J Clin Microbiol Infect Dis (2004) 23: 243–255