Pretomanid Pharmacokinetics in the Presence of Rifamycins: interim Results from a Randomized Trial among Patients with Tuberculosis.
Antimicrob Agents Chemother. 2020 Nov 23;:
Authors: Ignatius EH, Abdelwahab MT, Hendricks B, Gupte N, Narunsky K, Wiesner L, Barnes G, Dawson R, Dooley KE, Denti P, Assessing Pretomanid for Tuberculosis (APT) Study Team
Shorter, more potent regimens are needed for tuberculosis. The nitroimidazole pretomanid was recently approved for extensively drug-resistant tuberculosis in combination with bedaquiline and linezolid. Pretomanid may also have benefit as a treatment-shortening agent for drug-sensitive tuberculosis. It is unclear how and if it can be used together with rifamycins, key sterilizing first-line drugs.In this analysis, data were pooled from two studies: the Assessing Pretomanid for Tuberculosis (APT) trial, in which patients with drug-sensitive pulmonary TB received pretomanid, isoniazid, pyrazinamide, plus either rifampin or rifabutin versus standard of care under fed conditions and the AIDS Clinical Trials Group (ACTG) 5306 trial, a phase I study in healthy volunteers receiving pretomanid alone or in combination with rifampin under fasting conditions.In our population pharmacokinetic (PK) model, participants taking rifampin had 44.4 and 59.3% reduction in pretomanid AUC compared to rifabutin or pretomanid alone (due to 80 or 146% faster clearance) in APT and A5306, respectively. Median Cmax in the rifampin and rifabutin arms were 2.14 and 3.35 mg/liter, while median AUC0-24h were 30.1 and 59.5 mg·h/liter, respectively. Though pretomanid exposure in APT was significantly reduced with rifampin, AUC0-24 values were similar to those associated with effective treatment in registrational trials, likely because APT participants were fed with dosing, enhancing pretomanid relative bioavailability and exposures. Pretomanid concentrations with rifabutin were high, but in range with prior observations. While pretomanid exposures with rifampin are unlikely to impair efficacy, our data suggest that pretomanid should be taken with food if prescribed with rifampin.
PMID: 33229425 [PubMed - as supplied by publisher]