Pharmacokinetics and safety of TBAJ-876, a novel antimycobacterial diarylquinoline, in healthy subjects

Abstract

TBAJ-876, a second-generation diarylquinoline with greater antimycobacterial activity and a potentially better safety profile compared with bedaquiline, is under development for the treatment of drug-susceptible and drug-resistant tuberculosis (TB). A phase 1, first-in-human study of TBAJ-876, comprising a single-ascending dose (SAD) part including a food effect cohort, a multiple-ascending dose (MAD) part, and a relative bioavailability part of tablets versus oral suspension, was conducted on 137 healthy adults. A drug-drug interaction study was conducted on 28 healthy adults to evaluate the effects of TBAJ-876 on a cytochrome P450 3A4 substrate (midazolam) and a P-glycoprotein substrate (digoxin). TBAJ-876 was well-tolerated at single doses up to 800 mg and multiple doses up to 200 mg for 14 days. No deaths or serious adverse events occurred. No episodes of clinically significant prolongation of the QTc interval were observed. TBAJ-876 exposures were dose proportional in the SAD and MAD studies. TBAJ-876 exhibited multicompartmental pharmacokinetics (PK) with a long terminal half-life yielding quantifiable concentrations up to the longest follow-up of 10 weeks after a single dose and resulting in accumulation with multiple dosing. In the fed state, TBAJ-876 exposures approximately doubled with the tablet formulation, whereas M3 metabolite exposures decreased by approximately 20%. The relative bioavailability of TBAJ-876 was similar between tablets and the oral suspension at 100-mg doses. With co-administration of TBAJ-876, the AUC_0-inf of midazolam was unchanged and the C_max was reduced by 14%; the AUC_0-last of digoxin was increased by 51%, and the C_max was increased by 18%. These results support further investigation of TBAJ-876 for the treatment of tuberculosis.

Keywords: TBAJ-876; antimicrobial safety; diarylquinoline; pharmacokinetics; phase 1; tuberculosis.

Fig 1

Mean plasma concentrations over time of TBAJ-876, M3, and M2 in the SAD part of CL-001. Top: after escalating, single, fasted doses of TBAJ-876 administered as an oral suspension. Bottom: as single doses of 100 mg of TBAJ-876 administered as an oral suspension in fasted and fed states.

Fig 2

Mean plasma concentrations over time of TBAJ-876, M3, and M2 in the relative bioavailability part of CL-001, after single doses of 100 mg of TBAJ-876 administered as one 100-mg tablet fasted, one 100-mg tablet fed, and four 25-mg tablets fasted.

Fig 3

Mean plasma concentrations over time of TBAJ-876, M3, and M2 in the MAD part of CL-001. Top: Day 1. Bottom: Day 14. TBAJ-876 administered daily as an oral suspension under fed conditions.

Fig 4

DDI study, midazolam alone (Day 1) and with TBAJ-876 (Day 20). Mean plasma concentrations over time and geometric mean ratios with 90% confidence intervals (CIs).

Fig 5

DDI study, digoxin alone (Day 2) and with TBAJ-876 (Day 21). Mean plasma concentrations over time and geometric mean ratios with 90% confidence intervals (CIs).