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

Chevalier, Clémence; Perrimond-Dauchy, Sandrine; Dubourg, Julie; Fouqueray, Pascale; Bolze, Sébastien

doi:10.1007/s13318-020-00642-4

Cited by 12 publications

(10 citation statements)

References 20 publications

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“…Plasma concentrations of imeglimin were measured using a validated liquid chromatography with tandem mass spectrometry method with a lower limit of quantitation of 10 ng/ml, as described previously. 14 , 18 Concentrations expressed as hydrochloride salts were converted to concentrations of imeglimin base (molecular weight ratio: 0.810) before analysis.…”

Section: Methodsmentioning

confidence: 99%

“…In the current analysis, eGFR was derived based on the three‐variable Japanese 16 and CKD‐EPI 17 equations used for Japanese population and Western population, respectively. Plasma concentrations of imeglimin were measured using a validated liquid chromatography with tandem mass spectrometry method with a lower limit of quantitation of 10 ng/ml, as described previously 14,18 . Concentrations expressed as hydrochloride salts were converted to concentrations of imeglimin base (molecular weight ratio: 0.810) before analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Plasma elimination half‐life of imeglimin was 13.0 h with protein binding ratio of 1.2%–6.4% in healthy volunteers 13 . Renal transporters, organic cation transporter (OCT)2, multidrug and toxin extrusion (MATE)1, and MATE2‐K are involved in its tubular secretion in the kidneys, 13 but the clinical pharmacology study revealed that concomitant administration of an inhibitor of these transporters, cimetidine, showed no clinically relevant effect on imeglimin pharmacokinetics (PKs) 14 . Japanese 15 and Western 10 phase IIb studies have found that the minimum doses required for maximal effects are 1000 and 1500 mg b.i.d., respectively, and a slight increase in gastrointestinal adverse events was observed at the highest dose of 1500 mg b.i.d.…”

Section: Introductionmentioning

confidence: 99%

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Imeglimin population pharmacokinetics and dose adjustment predictions for renal impairment in Japanese and Western patients with type 2 diabetes

Tomita

Hansson²,

Mazuir

et al. 2022

Clinical Translational Sci

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Imeglimin is an orally administered first‐in‐class drug to treat type 2 diabetes mellitus (T2DM) and is mainly excreted unchanged by the kidneys. The present study aimed to define the pharmacokinetic (PK) characteristics of imeglimin using population PK analysis and to determine the optimal dosing regimen for Japanese patients with T2DM and chronic kidney disease (CKD). Imeglimin plasma concentrations in Japanese and Western healthy volunteers, and patients with T2DM, including patients with mild to severe CKD with an estimated glomerular filtration rate (eGFR) greater than 14 ml/min/1.73 m 2 were included in a population PK analysis. PK simulations were conducted using a population PK model, and the area under concentration‐time curve (AUC) was extrapolated with power regression analysis to lower eGFR. The influence of eGFR, weight, and age on apparent clearance and of dose on relative bioavailability were quantified by population PK analysis. Simulations and extrapolation revealed that the recommended dosing regimen based on the AUC was 500 mg twice daily (b.i.d.) for patients with eGFR 15–45 ml/min/1.73 m 2 , and 500 mg with a longer dosing interval was suggested for those with eGFR less than 15. Simulations revealed that differences in plasma AUCs between Japanese and Western patients at the same dose were mainly driven by a difference in the eGFR and that the plasma AUC after 1000 and 1500 mg b.i.d. in Japanese and Western patients, respectively, was comparable in the phase IIb studies. These results indicate suitable dosages of imeglimin in the clinical setting of T2DM with renal impairment.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Imeglimin population pharmacokinetics and dose adjustment predictions for renal impairment in Japanese and Western patients with type 2 diabetes

Tomita

Hansson²,

Mazuir

et al. 2022

Clinical Translational Sci

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“…The amount of IMEG excreted in the urine corresponds to the amount absorbed from the gastrointestinal tract. The pharmacokinetics of IMEG does not differ in Caucasian and Japanese individuals [19,20]. Yaribeygi et al [15] with own modification).…”

Section: Imeglimin -The First Oral Glimin Drugmentioning

confidence: 99%

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

Nowak

Grzeszczak

2022

Endokrynol Pol

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is multidirectional therapeutic intervention, including both carbohydrate and lipid control and normalization of blood pressure. This strategy has been shown to be beneficial for diabetic patients and contributes to the reduction of total mortality, cardiovascular deaths, and the risk of microangiopathy [3,4].In recent years, several new drugs have been added to the treatment of T2DM, and others are being intensively studied in experimental or clinical trials, producing not only hypoglycaemic effects but also affecting metabolic comorbidities. These include the following: -type II activin receptor modulators (bimagrumab); -amylin or dual amylin-calcitonin receptor agonists (pramlintide -amylin agonist); -adenosine monophosphate-activated protein kinase (AMPK) activator (A-769,662, thienopyridone); -fibroblast growth factor 21 analogues (pegbelfermin), fructose-1,6-bisphosphatase inhibitors (VK0612; MB07803); -novel GLP-1 receptor agonists (albiglutide, dulaglutide, exenatide, liraglutide, lyxisenatide, semaglutide, efpeglenatide, glutazumab, ITCA-650); -sodium-glucose co-transporters (SGLT-1 and -2) (SGLT-1 -licogliflozin, sotagliflozin and LX2761;

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“…It is poorly metabolized and has no inhibition or induction potential toward CYP450. Imeglimin is a substrate of MATE2-K and also a substrate and an inhibitor of OCT1, OCT2, and MATE1 transporters, but there is no clinically significant interaction when imeglimin is co-administered with either a substrate or an inhibitor of those transporters [23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of Imeglimin in Caucasian and Japanese Healthy Subjects

2022

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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.

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

Cited by 12 publications

References 20 publications

Imeglimin population pharmacokinetics and dose adjustment predictions for renal impairment in Japanese and Western patients with type 2 diabetes

Imeglimin population pharmacokinetics and dose adjustment predictions for renal impairment in Japanese and Western patients with type 2 diabetes

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

Pharmacokinetics of Imeglimin in Caucasian and Japanese Healthy Subjects

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