Transcript Phase I Issues for Novel TB Drugs

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