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 ( C max ) 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 C max and AUC 0–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.