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An Exposure-Response Perspective on the Clinical Dose of Pretomanid.

ABSTRACT: Pretomanid was approved by the U.S. FDA, via the limited population pathway for antibacterial and antifungal drugs, as part of a three-drug regimen with bedaquiline and linezolid for the treatment of extensively drug-resistant and treatment-intolerant or nonresponsive multidrug-resistant tuberculosis. The recommended dose of pretomanid is 200 mg once daily with food. The objective of this work was to retrospectively evaluate this recommended dose by means of exposure-response (E-R) modeling applied to outcomes of both efficacy and safety. Cox proportional-hazards modeling was used, with the steady-state average pretomanid concentration as the exposure metric. The efficacy outcome was time to sputum culture conversion (TSCC) to negative. The safety outcomes were times to the first occurrence of adverse events in classes selected from either pretomanid's investigator brochure or the new drug application (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 two adverse-event classes, vomiting (a single preferred term) and gastrointestinal (GI) symptoms (a collection of related terms). No significant E-R relationships were found for the single preferred terms nausea, alanine aminotransferase (ALT) increased, aspartate aminotransferase (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 exposures.

SUBMITTER: Nedelman JR

PROVIDER: S-EPMC7927811 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Bedaquiline (B), pretomanid (Pa) and linezolid (L) are key components of new regimens for treating rifampicin-resistant tuberculosis (TB). However, there is limited information on the global prevalence of resistance to these drugs and the impact of resistance on treatment outcomes. Mycobacterium tuberculosis (MTB) phenotypic drug susceptibility and whole-genome sequence (WGS) data, as well as patient profiles from 4 pretomanid-containing trials-STAND, Nix-TB, ZeNix and SimpliciTB-were used to investigate the rates of baseline resistance (BR) and acquired resistance (AR) to BPaL drugs, as well as their genetic basis, risk factors and impact on treatment outcomes. Data from >1,000 TB patients enrolled from 2015 to 2020 in 12 countries was assessed. We identified 2 (0.3%) participants with linezolid BR. Pretomanid BR was also rare, with similar rates across TB drug resistance types (0-2.1%). In contrast, bedaquiline BR was more prevalent among participants with highly resistant TB or longer prior treatment histories than those with newly diagnosed disease (5.2-6.3% vs. 0-0.3%). Bedaquiline BR was a risk factor for bacteriological failure or relapse in Nix-TB/ZeNix; 3/12 (25%, 95% CI 5-57%) participants with vs. 6/185 (3.2%, 1.2-6.9%) without bedaquiline BR. Across trials, we observed no linezolid AR, and only 3 cases of bedaquiline AR, including 2 participants with poor adherence. Overall, pretomanid AR was also rare, except in ZeNix patients with bedaquiline BR. WGS analyses revealed novel mutations in canonical resistant genes and, in 7 MTB isolates, the genetic determinants could not be identified. The overall low rates of BR to linezolid and pretomanid, and to a lesser extent to bedaquiline, observed in the pretomanid trials are in support of the worldwide implementation of BPaL-based regimens. Similarly, the overall low AR rates observed suggest BPaL drugs are better protected in the regimens trialed here than in other regimens combining bedaquiline with more, but less effective drugs.

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An Exposure-Response Perspective on the Clinical Dose of Pretomanid.

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