The Clinical Dose of Pretomanid: An Exposure-Response Perspective.

The objective of this work was to retrospectively evaluate that recommended dose by means of exposure-response (E-R) modeling applied to outcomes of both efficacy and safety. Cox proportional hazard modeling was used, with steady-state average pretomanid concentration as the exposure metric. The efficacy outcome was time to sputum culture conversion to negative (TSCC). The safety outcomes were times to first occurrence of adverse events in classes selected either from pretomanid's Investigator Brochure or from the NDA submission as recognized safety signals for pretomanid based on preclinical as well as clinical experience. Significant E-R relationships were found for TSCC and for two adverse event classes, Vomiting (a single preferred term) and GI Symptoms (a collection of related terms). No significant E-R relationships were found for the single preferred terms Nausea, ALT Increased, AST Increased, and Headache, and for the collections Hepatic Disorders, Transaminases Increased, Skin and Subcutaneous Tissue Disorders, and Headache. The results suggest that the recommended dose of pretomanid, 200 mg given in the fed state, is appropriate over the range of pharmacokinetic exposure. PMID: 33077660 [PubMed - as supplied by publisher]
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research