An Exposure-Response Perspective on the Clinical Dose of Pretomanid
Jerry R Nedelman1, David H Salinger2, Vishak Subramoney3
1TB Alliance, New York, New York, USA Jerry.Nedelman@tballiance.org.
Antimicrobial Agents and Chemotherapy
|October 20, 2020
Summary
This study confirms that the recommended 200 mg daily dose of pretomanid, when taken with food, is appropriate for treating multidrug-resistant tuberculosis. Exposure-response modeling showed this dose effectively balances treatment efficacy with patient safety outcomes.
Area of Science:
- Pharmacology and Infectious Diseases
- Drug Efficacy and Safety Evaluation
- Tuberculosis Treatment Research
Background:
- Pretomanid is approved for extensively drug-resistant tuberculosis (TB) as part of a three-drug regimen.
- The current recommended dose is 200 mg daily with food.
- Evaluating the dose-response relationship for efficacy and safety is crucial.
Purpose of the Study:
- To retrospectively evaluate the recommended 200 mg daily dose of pretomanid.
- To assess the exposure-response (E-R) relationship for both efficacy and safety outcomes.
- To determine if the current dosing is appropriate across pharmacokinetic exposure ranges.
Main Methods:
- Retrospective analysis using exposure-response (E-R) modeling.
- Cox proportional-hazards modeling applied to efficacy and safety data.
- Steady-state average pretomanid concentration used as the exposure metric.
Main Results:
- Significant E-R relationships found for time to sputum culture conversion (efficacy) and vomiting/gastrointestinal symptoms (safety).
- No significant E-R relationships identified for nausea, elevated liver enzymes (ALT, AST), or headache.
- The 200 mg dose in the fed state appears appropriate across observed pharmacokinetic exposures.
Conclusions:
- The established 200 mg daily dose of pretomanid with food is supported by exposure-response data.
- This dosing strategy effectively balances therapeutic benefits with manageable safety concerns.
- Further research can build upon these findings for optimized TB treatment regimens.
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