Poxel SA, 259/261 Avenue Jean Jaurès, 69007, Lyon, France.
Clin Pharmacokinet. 2020 Oct;59(10):1261-1271. doi: 10.1007/s40262-020-00886-y.
Imeglimin (IMEG) is the first in a novel class of oral glucose-lowering agents with a unique mechanism of action targeting mitochondrial bioenergetics. We assessed whether repeated co-administration of IMEG and either metformin (MET) or sitagliptin (SITA) would influence the pharmacokinetics of either MET or SITA in healthy Caucasian men.
Healthy Caucasian men received either MET 850 mg twice daily with placebo (n = 16) or SITA 100 mg once daily with placebo (n = 16) on days 1-6, followed by MET 850 mg twice daily with IMEG 1500 mg twice daily or SITA 100 mg once daily with IMEG 1500 mg twice daily on days 7-12. Pharmacokinetic parameters were determined from blood and urine; levels of all compounds were evaluated using liquid chromatography with tandem mass spectrometry.
Systemic exposure (AUC area under the plasma concentration-time curve over a dosing interval and maximum concentration) to MET was 14% and 10% lower, respectively, when administered with IMEG. Approximately 40% of MET was excreted unchanged in urine, decreasing to 34% when given with IMEG. The 90% confidence intervals for AUC and maximum concentration indicated no effect of co-administration on systemic exposure to MET. Mean AUC and maximum concentration of SITA were similar with or without IMEG. Median times to maximum concentration were 0.7 and 1.0 h and mean elimination half-lives were 8.2 and 8.7 h with and without IMEG, respectively. Systemic exposure to IMEG was similar to previous phase I studies.
Co-administration of IMEG with MET or SITA did not result in clinically relevant changes in systemic exposure to MET or SITA, although minor reductions in exposure (AUC and maximum concentration) and renal elimination were noted when MET was given with IMEG vs placebo.
EudraCT2009-014520-40 (MET-IMEG DDI) and EudraCT2010-022926-34 (SITA-IMEG DDI).
依格列净（IMEG）是一类新型的口服降糖药物，具有独特的靶向线粒体生物能量学作用机制。我们评估了在健康的白种男性中，重复给予 IMEG 与二甲双胍（MET）或西他列汀（SITA）联合用药是否会影响 MET 或 SITA 的药代动力学。
健康的白种男性在第 1-6 天分别接受 MET 850mg 每日两次联合安慰剂（n=16）或 SITA 100mg 每日一次联合安慰剂（n=16），然后在第 7-12 天分别接受 MET 850mg 每日两次联合 IMEG 1500mg 每日两次或 SITA 100mg 每日一次联合 IMEG 1500mg 每日两次。从血液和尿液中测定药代动力学参数；使用液质联用技术评估所有化合物的水平。
与 IMEG 联合给药时，MET 的全身暴露（AUC 药时曲线下面积/给药间隔和最大浓度）分别降低了 14%和 10%。大约 40%的 MET 以原形从尿液中排泄，当与 IMEG 联合给药时，排泄率降低至 34%。AUC 和最大浓度的 90%置信区间表明，联合用药对 MET 的全身暴露没有影响。有或没有 IMEG 时，SITA 的 AUC 和最大浓度相似。最大浓度的中位数时间分别为 0.7 和 1.0 小时，平均消除半衰期分别为 8.2 和 8.7 小时，有或没有 IMEG。与先前的 I 期研究相比，IMEG 的全身暴露情况相似。
与 MET 或 SITA 联合给药时，IMEG 并未导致 MET 或 SITA 的全身暴露发生临床相关变化，尽管与安慰剂相比，当 MET 与 IMEG 联合给药时，暴露量（AUC 和最大浓度）和肾脏清除率略有降低。
EudraCT2009-014520-40（MET-IMEG DDI）和 EudraCT2010-022926-34（SITA-IMEG DDI）。
