Safety, Tolerability, and Pharmacokinetics of Telacebec (Q203), a New Antituberculosis Agent, in Healthy Subjects

Abstract

Telacebec (Q203) is a potent drug candidate under clinical development for the treatment of drug-naïve and drug-resistant tuberculosis. The first-in-human randomized, placebo-controlled, double-blind, dose-escalation Phase 1A trial (Q203-TB-PI-US001) was conducted to evaluate the safety, tolerability, and pharmacokinetics of telacebec. A total of 56 normal, healthy, male and female subjects (42 active and 14 placebo) were enrolled in the study. The doses of telacebec were 10 mg (Cohort 1), 30 mg (Cohort 2), 50 mg (Cohort 3), 100 mg (Cohort 4), 200 mg (Cohort 5), 400 mg (Cohort 6), and 800 mg (Cohort 7) in a fasted state. Subjects participating in Cohort 4 were also enrolled in Cohort 8 to investigate the food effect on the pharmacokinetics of telacebec after a high-fat meal. In all subjects dosed with telacebec (10 to 800 mg), telacebec was well tolerated and did not lead to any significant or serious adverse events. Following a single oral administration of telacebec (10 to 800 mg), telacebec plasma concentration reached the maximal plasma concentration (C_max) in average 2.0 to 3.5 h and showed multi-exponential decline thereafter. The area under the plasma concentration versus time curve (AUC) was approximately dose-proportional. A significant increase in plasma concentrations was observed in the fed condition compared with the fasted condition with the geometric mean ratio of 3.93 for C_max. Moderate delay in T_max (4.5 h) was also observed in the fed condition. These results, combined with the demonstrated activity against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis, support further investigation of telacebec for the treatment of tuberculosis.

Keywords: Q203; pharmacokinetics; phase 1 trial; safety; telacebec; tolerability; tuberculosis.

FIG 1

Plasma concentration versus time profiles (A) for 48 h and (B) for 312 h after escalating single dose administration of telacebec from 10 mg to 800 mg in the fasted state. Data represent the mean ± SD (n = 6).

FIG 2

Systemic exposure represented by (A) C_max, (B) AUC_last, and (C) AUC_inf versus dose of telacebec after single administration of telacebec in the fasted state. Data represent the mean ± SD (n = 6).

FIG 3

Plasma concentration versus time profiles (A) for 48 h and (B) for 312 h after administration of telacebec (100 mg) under fasted and fed conditions. Data represent the mean ± SD (n = 6).