Imeglimin: A Clinical Pharmacology Review.

Imeglimin (PXL008, EMD-387008, Twymeeg®) is a first-in-class novel oral hypoglycemic agent, launched in Japan, for the treatment of type 2 diabetes mellitus. Its mechanism of action targets mitochondrial bioenergetics to ameliorate insulin resistance and to enhance ß-cell function. This review summarizes the properties underlying the pharmacokinetic profile of imeglimin, a small cationic drug belonging to the tetrahydrotriazine chemical class, with a complex mechanism of absorption involving an active transport through organic cation transporters (OCTs). Imeglimin absorption decreases when dose increases due to the saturation of the active uptake transport. Post absorption, imeglimin is rapidly and primarily distributed to organs and tissues, and has a half-life ranging from 9.03 to 20.2 h. Plasma protein binding of imeglimin is low, which explains the rapid distribution to the organs observed in all species. Imeglimin is excreted unchanged in urine, indicating a low extent of metabolism. Imeglimin is a substrate of multidrug and toxic compound extrusion (MATE) 2-K and a substrate and inhibitor of OCT1, OCT2, and MATE1. Clinical drug-drug interaction studies confirmed the absence of relevant clinical interaction with substrates or inhibitors of these transporters. Overall, the drug-drug interaction potential of imeglimin is low. Its pharmacokinetics profile has also been characterized in special populations, showing no influence of mild and moderate hepatic impairment but an impact of renal function on imeglimin renal clearance. Dosage adjustment is thus required in moderately and severely renally impaired patients. Imeglimin pharmacokinetics was shown to be insensitive to ethnicity and food intake and to have no effect on QTcF interval.

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 (t1/2) 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.

Pharmacokinetics of Imeglimin in Subjects with Moderate Hepatic Impairment.

BACKGROUND: Imeglimin is a novel oral antidiabetic drug used to treat type 2 diabetes, targeting the mitochondrial bioenergetics. Imeglimin is mainly excreted unchanged by the kidneys and is a substrate of organic cation transporters, which are expressed in the kidney and the liver. OBJECTIVE: The aim of this study was to assess the effect of hepatic impairment on the pharmacokinetics of imeglimin. METHODS: An open-label, single-dose, parallel-group study was carried out in seven subjects with normal hepatic function and seven subjects with moderate hepatic impairment who received a single dose of imeglimin 1000 mg. Blood and urine samples were collected up to 48 h after imeglimin administration. Pharmacokinetics were determined using non-compartmental methods. RESULTS: Imeglimin maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) in subjects with moderate hepatic impairment was 1.3-fold (90% confidence interval [CI] 1.05-1.60) and 1.5-fold (90% CI 1.19-1.82) higher than in subjects with normal hepatic function, but was not considered as clinically meaningful. Higher plasma exposure and amount of imeglimin renally excreted in moderate hepatic impaired subjects, associated with an unchanged elimination rate, suggests that this increase could be linked to a higher oral absorption and/or lower hepatic uptake in this population. CONCLUSIONS: Imeglimin was safe and well tolerated in all subjects. CLINICAL TRIAL REGISTRATION: EudraCT 2018-001950-83.

Pharmacodynamic effects of direct AMP kinase activation in humans with insulin resistance and non-alcoholic fatty liver disease: A phase 1b study.

AMPK is an energy sensor modulating metabolism, inflammation, and a target for metabolic disorders. Metabolic dysfunction results in lower AMPK activity. PXL770 is a direct AMPK activator, inhibiting de novo lipogenesis (DNL) and producing efficacy in preclinical models. We aimed to assess pharmacokinetics, safety, and pharmacodynamics of PXL770 in humans with metabolic syndrome-associated fatty liver disease. In a randomized, double-blind four-week trial, 12 overweight/obese patients with non-alcoholic fatty liver disease (NAFLD) and insulin resistance received PXL770 500 mg QD; 4 subjects received matching placebo. Endpoints included pharmacokinetics, hepatic fractional DNL, oral glucose tolerance testing, additional pharmacodynamic parameters, and safety. PK parameters show adequate plasma exposure in NAFLD patients for daily oral dosing. PXL770 decreases DNL-both peak and AUC are reduced versus baseline-and improves glycemic parameters and indices of insulin sensitivity versus baseline. Assessment of specific lipids reveals decrease in diacyglycerols/triacylglycerols. Safety/tolerability are similar to placebo. These results unveil initial human translation of AMPK activation and support this therapeutic strategy for metabolic disorders.

Lack of Drug-Drug Interaction Between Cimetidine, a Renal Transporter Inhibitor, and Imeglimin, a Novel Oral Antidiabetic Drug, in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: Imeglimin is a novel oral antidiabetic drug to treat type 2 diabetes, targeting the mitochondrial bioenergetics. In vitro, imeglimin was shown to be a substrate of human multidrug and toxic extrusion transporters MATE1 and MATE2-K and organic cation transporters OCT1 and OCT2. The objective of the study was to assess the potential drug-drug interaction between imeglimin and cimetidine, a reference inhibitor of these transporters. METHODS: A phase 1 study was carried out in 16 subjects who received a single dose of 1500 mg imeglimin alone on day 1 followed by a 6-day treatment (day 5 to day 10) with cimetidine 400 mg twice daily. On day 8, a single dose of imeglimin was co-administered with cimetidine. Blood and urine samples were collected up to 72 h after each imeglimin administration. Pharmacokinetic parameters were determined using non-compartmental methods. RESULTS: Imeglimin maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 1.3-fold [90% CI (1.12-1.62) and (1.10-1.46) for Cmax and AUC0-last, respectively] higher when imeglimin was co-administered with cimetidine but this increase was not considered clinically relevant. This increase could be mainly explained by a reduction in renal elimination, mediated through the cimetidine inhibition of renal MATE1 transporter. Imeglimin taken alone or with cimetidine was safe and well tolerated in all subjects. CONCLUSIONS: No clinically significant drug-drug interaction exists between imeglimin and cimetidine, a reference inhibitor of MATE1, MATE2-K, OCT1 and OCT2 transporters. CLINICAL TRIAL REGISTRATION: EudraCT 2018-001103-36.