1. 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

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

3. Outline TB Drug Development Clinical Pharmacology Assessments –Studies to characterize clinical pharmacology In Vitro studies In Vivo studies –Evaluation of Exposure-Response Relationships Summary

4. 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

5. 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

6. 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

7. 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

8. 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

9. Drug Interaction Studies (cont.) Evaluate potential of the TB drug to interact with the major CYP450 enzymes: CYP1A2 CYP2C8 CYP2C9 CYP2C19 CYP2D6 CYP3A4/5

10. An approach to study CYP-Based Drug-Drug Interaction Studies YesNo YesNo YesNo In Vitro metabolism Information CYP 1A2, 2C8, 2C9, 2C19, 2D6, 3A 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? YesNo Presence of significant interaction?

11. Drug Interaction Studies (cont.) DrugMetabolismExcretionKnown drug interactions IsoniazidAcetylation75-95% in urineDrugs metabolized by CYP1A2, 2C9, 2C19, 2A6 and 3A PyrazinamidePredominantly hydrolyzed to 5-OH- pyrazinoic acid 3% in urineNo known interactions with drugs metabolized by the CYP enzyme system Ethambutol8-15% metabolized by liver 75% in urineNo known CYP450 interactions RifampinMetabolized to 25- desacetyl-rifampin 30% in urinePotent CYP450 inducer (variety of drugs) Currently marketed TB drugs

12. 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

13. 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

14. Drug Interaction Studies (cont.) Study Design Considerations End Points –PK parameters for systemic exposure (AUC, C max, T max ) and disposition (CL, V d, T ½ ) –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, C max ) in presence and absence of interacting drug

15. 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

16. 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

17. 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) –C max /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 DrugPK/PD parameter IsoniazidC max /MIC 1 RifampinAUC/MIC 2,3 RifapentineUnknown PyrazinamideUnknown

18. 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

20. Right drug? Clinical Pharmacology & Biopharmaceutics Right patient? Right dose/dosage regimen?

21. Questions???

22. Backup slides

23. PK/PD of INH, Rifampin and Pyrazinamide Eur J Clin Microbiol Infect Dis (2004) 23: 243–255

24. PK/PD of Fluoroquionolones Eur J Clin Microbiol Infect Dis (2004) 23: 243–255