Pharmacokinetics of Imeglimin in Caucasian and Japanese Healthy Subjects

BACKGROUND: Imeglimin is a first-in-class novel oral antidiabetic marketed in Japan as TWYMEEG(®) to treat type 2 diabetes mellitus. Its mode of action is distinct from all other anti-hyperglycemic classes. OBJECTIVE: To assess the pharmacokinetic and safety profile of imeglimin in Caucasian and Japanese healthy individuals. METHODS: Two randomized placebo-controlled phase 1 clinical studies were conducted in Caucasian subjects after single (250–8000 mg) and multiple (250–2000 mg twice daily) ascending doses and in Japanese subjects after single (500–6000 mg) and multiple (500–2000 mg twice daily) ascending doses. Imeglimin plasma and urine concentrations were measured. RESULTS: All imeglimin doses achieved maximal concentration between 1 and 3.5 h in Caucasians, and 1.5 and 3 h in Japanese subjects. The elimination half-lives (t(1/2)) were dose-independent and means ranged between 9.03 and 20.2 h for Caucasians, and 4.45 and 12 h for Japanese subjects. Dose-normalized area under the plasma concentration-time curve decreased with dose in the 250–8000 mg and in the 500–6000 mg dose range in Caucasians and Japanese, respectively, suggesting a dose-dependent but less than dose-proportional effect in imeglimin exposure. Plasma accumulation was minimal following repeated dosing, and food did not affect the pharmacokinetics in either population. Exposures were generally similar between Caucasian and Japanese subjects with less than 20% difference, although there was a tendency for exposures in Japanese to be slightly higher. Imeglimin had an acceptable safety and tolerability profile, with dose-dependent mild gastrointestinal adverse events. CONCLUSION: Imeglimin was safe and well tolerated in these two phases 1 studies, with pharmacokinetics comparable between the two populations. CLINICAL TRIAL REGISTRATIONS: EudraCT 2005-001946-18 and 2014-004679-21. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40261-022-01181-3.