Pretomanid Pharmacokinetics in the Presence of Rifamycins: Interim Results from a Randomized Trial among Patients with Tuberculosis

Abstract

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.

Promise and Peril of Pretomanid–Rifamycin Regimens for Drug-susceptible Tuberculosis

“…In contrast, the pretomanid–rifampin combination likely decreased pretomanid exposures such that its effect on time-to-culture conversion in liquid culture was observed as a nonsignificant trend. The published interim pharmacokinetic analysis supports this hypothesis, given that pretomanid exposure as measured by the area under the concentration time curve was 44.4% lower in the pretomanid–rifampin arm than in the pretomanid–rifabutin arm, driven by an 80% increase in clearance ( 11 ). Another potential explanation for the observed differences in efficacy, as raised by the authors, may be that rifabutin exhibited different efficacy than rifampin; however, a previous systematic review did not show a difference between these rifamycins with respect to sputum culture conversion, cure, or relapse ( 12 ).…”

“…Its substitution for ethambutol in drug-susceptible TB, however, does have caveats; pretomanid has a known drug–drug interaction with rifampin, a potent inducer of the cytochrome P450 system, which decreases pretomanid plasma concentrations. Interim pharmacokinetic analysis of pooled data from the APT trial and the AIDS Clinical Trials Group A5306 trial confirmed that rifabutin averts the drug–drug interaction with pretomanid ( 11 ).…”

New and Repurposed Drugs for the Treatment of Active Tuberculosis: An Update for Clinicians

“…SimpliciTB is the continuation of the STAND trial that was changed from PaMZ into BPaMZ when the results came available of the NC005 trial. Further trials with PA are the phase 3 ZeNix trial (aimed to reduce linezolid toxicity) and the phase 2B APT trial evaluating PA added to a first-line regimen with either rifampicin or rifabutin, isoniazid, and pyrazinamide [ 63 ].…”

Profiling Pretomanid as a Therapeutic Option for TB Infection: Evidence to Date

“…A recent study suggests that this increased exposure in the fed state may be leveraged to negate the reduction expected with co-administration of rifampin. 63 …”