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Transcript
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 In Vitro metabolism Information CYP 1A2, 2C8, 2C9, 2C19, 2D6, 3A <Studies in human tissues> NME not a substrate or NME a substrate but contribution of pathway not major NME is a substrate and contribution of pathway to elimination major or unclear NME is an inducer or inhibitor or no in vitro data NME not an inducer or inhibitor Label as such based on in vitro and in vivo disposition data Conduct in vivo studies with most potent inhibitor(s)/inducer(s) Conduct in vivo studies with most sensitive/specific substrate(s) Label as such based on in vitro data Presence of significant interaction? Yes Presence of significant interaction? No Yes Study other inhibitors/inducers selected based on likely coadministration Dosage Adjustment needed? Yes No No further studies needed General Label based on in vitro and in vivo data No Study other substrates selected based on likely co-administration narrow therapeutic range Dosage Adjustment needed? Yes No No further studies needed general label based on in vitro and in vivo data Drug Interaction Studies (cont.) Currently marketed TB drugs Drug Isoniazid Metabolism Acetylation Excretion Known drug interactions 75-95% in urine Drugs metabolized by CYP1A2, 2C9, 2C19, 2A6 and 3A Pyrazinamide Predominantly hydrolyzed to 5-OHpyrazinoic 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 25desacetyl-rifampin 30% in urine Potent CYP450 inducer (variety of 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 antiinfective 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 Summary Summary Phase I Studies Phase I Studies •Clinical Pharmacology •Clinical Pharmacology Phase II Studies Phase II Studies • Dose ranging • Dose ranging • Exposure-response • Exposure-response • Optimal dose selection Phase III Studies Phase III Studies Approval Approval • Optimal dose selection • Safety & Efficacy • Safety & Efficacy • Exposure-response •Exposure-response • Population •Population Pharmacokinetics Pharmacokinetics 21 21 Clinical Pharmacology & Biopharmaceutics Right drug? 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