DISCUSSION
TB, toxicities, TEAEs, pruritus, headache, pulmonary TB
EVENTS
The development of more effective and tolerable anti-TB regimens with shorter treatment durations requires new anti-TB agents (In general, a less than dose-proportional increase in plasma exposure was observed for OPC-167832, as demonstrated by a slope parameter value less than 1, which was likely due to a decrease in bioavailability with increasing dose (In preclinical studies, OPC-167832 was characterized by high bactericidal activity (Sputum LAM has been proposed to be a potential biomarker to quantify bacterial load during TB treatment (With no reported dose-limiting toxicities, tolerability of OPC-167832 was confirmed in healthy participants at single doses up to 480 mg and in participants with TB for multiple doses up to 90 mg. Nearly all reported TEAEs in the three studies were mild in intensity and self-limiting, with only headache and pruritus occurring among the most commonly reported events in at least two of the studies. Alterations in physical examination findings, vital signs, clinical laboratory results, and ECGs were minimal in all participants (including no evidence of clinically significant QTc prolongation). Overall, these favorable tolerability and safety findings for OPC-167832 were consistent with the safety profiles of other carbostyril-based drugs (The promising safety profile and potent bactericidal activity observed with monotherapy in the current MAD/EBA study encourages further clinical development of OPC-167832, including evaluation of the effect of regimens containing OPC-167832 in sputum culture conversion and relapse-free cure. A second stage of the phase I/IIa study, ongoing at the time of this report, is comparing three combination drug regimens—OPC-167832/delamanid, OPC-167832/bedaquiline and OPC-167832/delamanid/bedaquiline—in participants with pulmonary TB. OPC-167832 is being administered in the above combinations at once-daily doses of 30 mg, and results from this trial are forthcoming.To summarize, in these first in-human studies, OPC-167832 met expectations raised during its preclinical development by exhibiting high EBA in participants with drug-susceptible, smear-positive, pulmonary TB, as well as favorable pharmacokinetic, tolerability, and safety profiles. Future evaluation of OPC-167832-containing regimens on sputum culture conversion and relapse-free cure are warranted.