First-in-human study of the benzothiazinone and DprE1 inhibitor BTZ-043, a novel drug candidate for the treatment of Tuberculosis.

Objectives: This first-in-human, single ascending dose study evaluated the safety, tolerability and pharmacokinetics (PK) of the decaprenylphosphoryl-β-D-ribose-2'-epimerase (DprE1) inhibitor BTZ-043.

Methods: BTZ-043 was administered as an oral suspension at doses of 125, 250 and 500 mg along with placebo to healthy participants. Safety assessments included evaluation of laboratory parameters, vital signs, physical and neurological examination, and 12-lead ECG. Blood samples for PK assessment in plasma were collected over a 36 h post-dose period. PK parameters were calculated using non-compartmental analysis for parent BTZ-043, metabolites M1 and M2, and BTZ-043_total (sum of BTZ-043 and M2) in plasma.

Results: Thirty participants completed the study. All administered BTZ-043 doses were safe and well tolerated. Nervous system disorders (dizziness and headache) and vascular disorders (hypertension and hot flush) were the most frequently reported adverse events (AEs). All AEs were mild or moderate. The parent compound BTZ-043 was rapidly metabolized to metabolite M2 (unknown activity), with median time to maximum concentration in plasma (t _max) of 1.5 h (1-2 h). BTZ-043 and M2 had a short half-life. The second main inactive metabolite M1 showed a median t _max of 7-8.5 h and a geometric mean half-life of 8.4-9.0 h. The increases in AUC and maximum concentration of drug in plasma (C _max) of BTZ-043 were more than dose-proportional, and those of BTZ-043_total were almost dose-proportional. No relevant differences in systemic exposures between males and females were observed.

Conclusions: BTZ-043 was safe, well tolerated and underwent rapid absorption, metabolism and elimination, supporting further clinical development.