Drug Development Division, Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan.
Pharmetheus AB, Uppsala, Sweden.
Clin Transl Sci. 2022 Apr;15(4):1014-1026. doi: 10.1111/cts.13221. Epub 2022 Jan 17.
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 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 , 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.
依格列净是一种新型口服降糖药物，可用于治疗 2 型糖尿病（T2DM），主要以原形经肾脏排泄。本研究旨在采用群体药代动力学（PK）分析方法确定依格列净的 PK 特征，并为 T2DM 合并慢性肾脏病（CKD）的日本患者确定最佳给药方案。本研究纳入了日本和西方健康志愿者、T2DM 患者（包括 eGFR 大于 14ml/min/1.73m 的轻至重度 CKD 患者）的依格列净血药浓度，进行群体 PK 分析。采用群体 PK 模型进行 PK 模拟，并采用幂回归分析对较低 eGFR 时的 AUC 进行外推。通过群体 PK 分析，定量评估了 eGFR、体重和年龄对表观清除率以及剂量对相对生物利用度的影响。模拟和外推结果表明，基于 AUC 的推荐给药方案为 eGFR 为 15-45ml/min/1.73m 的患者，500mg 每日 2 次（bid）；eGFR 小于 15ml/min/1.73m 的患者，建议使用更长的给药间隔。模拟结果表明，相同剂量下日本和西方患者间的 AUC 差异主要由 eGFR 差异所致，在 IIb 期研究中，日本和西方患者分别接受 1000mg 和 1500mg bid 治疗后，其 AUC 相似。这些结果表明，依格列净在 T2DM 合并肾损害的临床治疗中具有合适的剂量。
