Indicated as part of a three-drug oral combination.
Pretomanid is a nitroimidazole antimicrobial for the treatment of extensively drug resistant (XDR-TB) and treatment-intolerant or non-responsive multidrug-resistant pulmonary tuberculosis (MDR-TB). It is indicated as part of a three-drug oral combination with bedaquiline and linezolid, or the BPaL regimen. BPaL offers novel treatment for a patient population with poor prognosis and limited treatment options.
Pretomanid has been studied alone and in combination in 19 clinical trials with 1,168 total trial participants. Pretomanid has been evaluated in a pivotal phase 3 open-label trial, Nix-TB, as part of the BPaL regimen. Nix-TB enrolled 109 patients with XDR-TB as well as treatment-intolerant or non-responsive MDR-TB from three sites in South Africa. Patients were treated with bedaquiline 400 mg once daily for 2 weeks then 200 mg 3 times per week, plus pretomanid 200 mg once daily and linezolid 1200 mg once daily for 6 months. The primary outcome measure looked at incidence of bacteriologic failure, relapse, or clinical failure through follow-up until 6 months after treatment completion. Pretomanid demonstrated favorable outcomes of relapse-free cure status in 95 of the first 107 patients 6 months after end of treatment.1,2
The Nix-TB study also assessed the safety of pretomanid in combination with bedaquiline and linezolid. Of the 109 patients treated in this study, there were 8 deaths. Six patients died while receiving treatment and two died during follow-up. The most common adverse reactions reported in >5% of patients included peripheral neuropathy, acne, anemia, nausea, vomiting, musculoskeletal pain, and headache. Twenty-eight percent of study participants experienced increased transaminases; however, all patients in this group were able to continue therapy and complete the full treatment course. Peripheral neuropathy, a known side effect of linezolid, occurred in 81% of study patients but did not lead to discontinuation of the entire study regimen. Linezolid is likely responsible for most adverse events and all dose modifications.1,2
ZeNix, the most recent clinical trial involving BPaL, aims to determine whether the efficacy of BPaL can be maintained while reducing toxicity with a lower dose and shorter duration of linezolid. ZeNix is a phase 3, multi-center, partially-blinded, randomized clinical trial with four parallel treatment groups. Linezolid treatment dose and duration will be double blinded. Results from this study will be released on a rolling basis.3
Pretomanid is dosed 200 mg orally once daily in combination with bedaquiline and linezolid for 26 weeks total. Combination dosing includes bedaquiline 400 mg orally once daily for two weeks followed by 200 mg 3 times per week for 24 weeks, plus linezolid 1,200 mg orally once daily for 26 weeks. BPaL is administered by directly observed therapy. Dose adjustment recommendations for renal and hepatic impairment are not included in the manufacturer’s labeling, as they have not been studied in these limited and specific patient populations.1
1. Pretomanid [package insert]. New York, NY: The Global Alliance for TB Drug Development; 2019.
2. ClinicalTrials.gov Identifier: NCT02333799. Accessed: August 27, 2019.
3. ClinicalTrials.gov Identifier: NCT03086486. Accessed: August 27, 2019.