Pharmacokinetics of Imeglimin in Caucasian and Japanese Healthy Subjects

Abstract

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.

Pharmacokinetics and Safety of Imeglimin in Japanese Patients With Impaired Renal Function

“…First, this was a single‐dose study that included only Japanese participants; the projection of C max and AUC after multiple doses assumed no abnormal imeglimin accumulation after multiple doses, and safety after multiple doses was not confirmed. Of note, absence of abnormal accumulation and safety after multiple imeglimin doses have been confirmed in other clinical studies, including participants with renal impairment 12,16–19,27 . No clinically relevant differences in imeglimin PK have been observed between Japanese and White patients 12,13 .…”

“…In humans, unchanged imeglimin is the major circulating radioactive component in plasma following oral administration of [ 14 C]imeglimin (93% of plasma total radioactivity area under the plasma concentration‐time curve [AUC]) 11 . Other PK studies have shown that as imeglimin dose increases, the dose‐normalized AUC decreases, as does the urinary excretion rate; therefore, the level of absorption decreases with increased dosing 12,13 . Bioavailability is moderate to high in rats and dogs (30% and 76%, respectively) 11 and, at the clinical dose, estimates using the urinary excretion rate indicate it is ≈40% in humans 12 .…”

Imeglimin: a new antidiabetic drug with potential future in the treatment of patients with type 2 diabetes

“…Imeglimin is a drug intended for oral administration. The half-life has been shown to be 10-20 hours in healthy volunteers [6,16]. Until now, only a few studies that report on the absorption, metabolism, and elimination of IMEG from the body have been conducted.…”

“…After oral administration of IMEG, its absorption occurs by both passive and active transport and lasts up to 6 hours [6]. The bioavailability after oral administration of IMEG drug ranges from 50 to 20%, and it depends on the dose of the drug administered (100-6000 mg) -it decreases with the drug dose increasing [16,17]. Imeglimin bonds to plasma proteins only to a small extent (1-8%) [18].…”

“…Imeglimin is eliminated from the body in a biphasic manner with an initial rapid phase followed by a slower elimination phase. The hepatic metabolism of IMEG is very low, so it is excreted almost completely unchanged in urine [16]. The amount of IMEG excreted in the urine corresponds to the amount absorbed from the gastrointestinal tract.…”