Antituberculosis Macozinone Extended-Release Tablets To Enhance Bioavailability: a Pilot Pharmacokinetic Study in Beagle Dogs

Abstract

Macozinone (MCZ) is the newest first-in-class clinical-stage benzothiazinone-based drug candidate for the treatment of tuberculosis. Yet, the extremely low oral bioavailability of MCZ, a major problem in clinical trials, needed to be addressed, and we are pleased to present our attempts to solve this issue.

Antibiotics in the clinical pipeline as of December 2022

“…Macozinone ( 53 ) is a second generation analog of BTZ043 ( 34 , Fig. 6 ) with the same MoA (inhibition of the mycobacterial cell wall biosynthesis enzyme DprE1) with superior physicochemical properties [ 289 ]; however, efforts have been undertaken to improve its PK and PD properties [ 290 ].…”

Synthesis, structures, reactivity and medicinal chemistry of antitubercular benzothiazinones

“…117 In a recent proof-of-concept study, Koryakova et al compared the pharmacokinetics of PBTZ169 formulated as immediate-release dispersible tablets and two-types of extended-release (mucoadhesive) tablets 123 in a small sample size ( n = 5) group of healthy beagle dogs. 120 The authors concluded that one type of extended-release tablets in fed state improved the pharmacokinetic parameters of PBTZ169 compared with the immediate release tablet in the fasted state.…”

“…117 PBTZ169 was used as hydrochloride salt. 119,120 Koryakova et al mentioned that various water-soluble salts, the use of surfactants or particle size reduction failed to improve This journal is © The Royal Society of Chemistry 2023 the bioavailability of PBTZ169. 120 Li et al, however, reported some progress for the benzothiopyranone analogue of PBTZ169 through solubility-driven optimization of salt forms with pharmaceutically acceptable anions.…”

“…119,120 Koryakova et al mentioned that various water-soluble salts, the use of surfactants or particle size reduction failed to improve This journal is © The Royal Society of Chemistry 2023 the bioavailability of PBTZ169. 120 Li et al, however, reported some progress for the benzothiopyranone analogue of PBTZ169 through solubility-driven optimization of salt forms with pharmaceutically acceptable anions. 121 Compared with the freebase compound, in particular the hydrogen maleate salt 52 (Fig.…”

A Review of Antibacterial Candidates with New Modes of Action

“…MoA studies showed that the BTZs underwent in vivo reduction of the nitro group, then formed a semimercaptal covalent bond with cysteine-387 of DprE1. − A phase 2 trial (NCT05926466) evaluating three BTZ-043 ( 10 )-containing TB drug regimens started in September 2023. Macozinone ( 11 ) (PBTZ169) is another BTZ that acts via the same MoA but possesses improved physicochemical properties. , It was evaluated in a phase 2 early bactericidal activity (EBA) TB trial (NCT03334734) that started in 2016 but was terminated in 2018 after enrolling only 16 patients. Evidence suggests that BTZs can be dearomatized through the formation of a Meisenheimer complex, reducing their in vivo half-lives. − …”