Phase 1 Study of the Effects of the Tuberculosis Treatment Pretomanid, Alone and in Combination With Moxifloxacin, on the QTc Interval in Healthy Volunteers

Abstract

Tuberculosis (TB) continues to be a serious threat to public health throughout the world. Newer treatments are needed that could offer simplified regimens with activity against both drug-sensitive and drug-resistant bacilli, while optimizing safety. Pretomanid (PA-824), a nitroimidazooxazine compound, is a new drug for the treatment of pulmonary TB that was recently approved in the United States and Europe in the context of a regimen combined with bedaquiline and linezolid. This phase 1 double-blind, randomized, placebo-controlled crossover study specifically examined the effect of single-dose administration of pretomanid 400 or 1000 mg and pretomanid 400 mg plus moxifloxacin 400 mg on the QTc interval in 74 healthy subjects. Subjects were fasting at the time of drug administration. Pretomanid concentrations following single 400-or 1000-mg doses were not associated with any QT interval prolongation of clinical concern. Moxifloxacin did not alter the pharmacokinetics of pretomanid, and the effect of pretomanid 400 mg plus moxifloxacin 400 mg on the individually corrected QT interval was consistent with the effect of moxifloxacin alone. Both drugs were generally well tolerated. Although supratherapeutic exposure of pretomanid relative to the now-recommended dosing with food was not achieved, these findings contribute to the favorable assessment of cardiac safety for pretomanid.

Safety and pharmacokinetic profile of pretomanid (PA-824) in healthy Chinese participants: Results of a phase I single dose escalation study

“…In general, these ndings in a Chinese population were comparable to previous ndings of Phase I studies in non-Chinese populations. [8][9][10][11][12][13] Most of the AEs observed in this trial were reported in previously published studies of pretomanid and, overall, the safety pro le of pretomanid in this trial was consistent with previous ndings. [8-16, 18] In a pooled analysis of TEAEs in non-Chinese subjects who received pretomanid in prior phase 1 studies (single or multiple doses), the most common TEAEs by system organ class were nervous system disorders (37.7%), gastrointestinal disorders (24.2%), and investigations (21.8%).…”

“…[7] Results from a total of eight phase I trials of single and repeated administration of pretomanid have been published (CL-001, CL-002, CL-003, CL-005, CL-006, CL-009, A5306 and DMID 10-0058), including a total of 289 healthy participants. [8][9][10][11][12][13] These previous studies investigated single doses of pretomanid ranging from 50 to 1500 mg and repeated doses ranging from 200 to 1000 mg/day from 7 to 14 days. Furthermore, the PK pro le of pretomanid was also investigated in two phase IIa studies (CL-007 and CL-010) of pretomanid conducted in tuberculosis patients.…”

Toxicity and toxicokinetic assessment of an anti-tubercular drug pretomanid in cynomolgus monkeys

“…In Phase I studies in healthy patients, no cardiovascular-related effects on 2-lead cardiac profiles or 12-lead ECG parameters, including heart rate and QT interval, were noted after single doses of pretomanid up to 1500 mg or seven repeat doses up to 600 mg [16] . In a randomized, double-blind, placebo- and positive controlled, crossover, thorough QT study of pretomanid, single doses of pretomanid up to 1000 mg caused no QTc prolongation of clinical concern in healthy subjects [17] . Pretomanid monotherapy during two early bactericidal activity (EBA) studies up to 1200 mg for 14 days was well tolerated with no clinically significant QTc changes [18] , [19] .…”

QT-Interval Prolongation in the Treatment of Drug-Resistant Tuberculosis

“…Li и соавт. [85] изучили влияние монотерапии Ра (400 и 1000 мг) и комбинации Ра (400 мг) с Mfx (400 мг) на интервал QTc у 74 субъектов. Моксифлоксацин не влиял на фармакокинетику Ра, а действие комбинации препаратов соответствовало эффекту одного Mfx.…”