Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany.
Boehringer Ingelheim International GmbH, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.
Clin Drug Investig. 2018 Aug;38(8):737-750. doi: 10.1007/s40261-018-0660-2.
Schizophrenia and Alzheimer's disease are characterised by abnormalities in glutamatergic pathways related to N-methyl-D-aspartate receptor hypofunction. Glycine is an N-methyl-D-aspartate receptor co-agonist; inhibition of glycine transporter 1 may improve N-methyl-D-aspartate receptor function. This phase I, randomised, two-part study evaluated the safety, tolerability and pharmacokinetic profile of BI 425809, a novel glycine transporter 1 inhibitor, in healthy male and female volunteers.
Part 1 evaluated BI 425809 10, 25, 50 or 75 mg once daily or 75 mg twice daily in young subjects, and 25 mg or 50 mg once daily in elderly subjects. Each dose group comprised 12 subjects who received BI 425809 (n = 9) or placebo (n = 3) for 14 days (day 1: single dose; days 4-14: multiple dosing). Part 2 compared pharmacokinetic profiles in 12 subjects who received a single dose of BI 425809 25 mg in the morning and evening.
Pharmacokinetic profiles were similarly shaped for all dose groups. Median time to maximum plasma concentration was 3.0-4.5 h with steady state being reached between days 6 and 10. Pharmacokinetic parameters demonstrated dose linearity at the predicted therapeutic exposure range of BI 425809 ≤ 25 mg once daily, but increased less than dose proportionally for ≥ 50 mg once daily. All reported adverse events were of mild-to-moderate intensity, 51/84 (61%; part 1) subjects had one or more treatment-related adverse event, no serious adverse events occurred and no dose dependency was observed.
Pharmacokinetic properties support both morning and evening dosing. BI 425809 was generally well tolerated at all tested doses. CLINICALTRIALS.
NCT02337283.
精神分裂症和阿尔茨海默病的特征是与 N-甲基-D-天冬氨酸受体功能低下相关的谷氨酸能途径异常。甘氨酸是 N-甲基-D-天冬氨酸受体协同激动剂；抑制甘氨酸转运体 1 可能会改善 N-甲基-D-天冬氨酸受体功能。这项 I 期、随机、两部分研究评估了新型甘氨酸转运体 1 抑制剂 BI 425809 在健康男性和女性志愿者中的安全性、耐受性和药代动力学特征。
第 1 部分评估了 BI 425809 在年轻受试者中每日一次 10、25、50 或 75mg，或每日两次 75mg，以及在老年受试者中每日一次 25 或 50mg。每个剂量组包括 12 名接受 BI 425809（n=9）或安慰剂（n=3）治疗 14 天的受试者（第 1 天：单次剂量；第 4-14 天：多次剂量）。第 2 部分比较了 12 名受试者在早上和晚上单次服用 BI 425809 25mg 的药代动力学特征。
所有剂量组的药代动力学特征相似。达到最大血浆浓度的中位时间为 3.0-4.5h，在第 6-10 天达到稳态。药代动力学参数在预测的 BI 425809 治疗暴露范围内呈线性，≤25mg 每日一次，但每日一次≥50mg 时，增加幅度小于剂量比例。所有报告的不良事件均为轻度至中度，84 名受试者中的 51 名（61%）有 1 次或多次与治疗相关的不良事件，无严重不良事件发生，且未观察到剂量依赖性。
药代动力学特性支持早晚给药。BI 425809 在所有测试剂量下均具有良好的耐受性。临床试验。
NCT02337283。
