一项在健康日本人中开展的mGluR2负变构调节剂MK-1942的1期研究，以灵活评估包括CYP2C19表型在内的因素。
完整摘要 · 中文译文
MK-1942 是一种代谢型谷氨酸受体 2 的负变构调节剂，曾被研究用于治疗阿尔茨海默病和抑郁症。使用重组人 CYP 和基因分型人肝细胞进行的非临床研究提示，CYP2C19 参与 MK-1942 的代谢。鉴于日本人群中不同 CYP2C19 多态性的高发生率，一项在健康日本受试者中开展的 1 期单次和多次给药研究为确定 CYP2C19 表型对 MK-1942 临床药代动力学的影响提供了机会。此外，由于在非日本人群中进行的首次人体研究显示，高脂餐后给药暴露量降低，我们在日本研究中进一步考察了低脂餐对药代动力学的影响。该研究设计具有灵活性，可根据总体安全性和药代动力学数据为多次给药组选择剂量。在日本受试者中口服单次和多次剂量 MK-1942 总体耐受良好。空腹与餐后（低脂餐）状态下的 AUC0-inf 相当。单次给予 MK-1942 后，CYP2C19 慢代谢型（PM）受试者的 AUC0-inf 较快代谢型（EM）受试者增加约 70%。因此，决定按 CYP2C19 表型分别进行多次给药试验，而非将其合并为一个组。与单次给药结果的预期相反，各 CYP2C19 表型间的稳态暴露量相似。这些数据支持了后续全球 2 期研究中允许给药前后摄入低脂餐且无需调整剂量的设计。 对任何CYP2C19表型进行校正。
完整摘要 · 英文原文
MK-1942 is a negative allosteric modulator of the metabotropic glutamate receptor 2 that was investigated for the treatment of Alzheimer's disease and depression. Nonclinical studies with recombinant human CYPs and genotyped human hepatocytes suggested that CYP2C19 is involved in the metabolism of MK-1942. Given the high incidence of different CYP2C19 polymorphisms in the Japanese population, a Phase 1 single and multiple dose study in healthy Japanese participants provided an opportunity to determine the involvement of CYP2C19 phenotype on the clinical PK of MK-1942. Also, since a first-in-human study in non-Japanese showed a decrease in exposures after administration with high-fat meal, we further tested an effect of low-fat meal on PK in the Japan study. The study was designed with flexibility which enabled dose selection for the multiple dose panels, based on the totality of safety and PK data. Oral administration of single and multiple doses of MK-1942 in Japanese participants was generally well tolerated. AUC0-inf was comparable between fasted and fed (low-fat meal) state. Following a single dose of MK-1942, AUC0-inf was ~70% increased in CYP2C19 poor metabolizer (PM) vs. extensive metabolizer (EM). Therefore, a decision was made to test the multiple dose separately for each CYP2C19 phenotype, rather than grouping them into a single panel. As opposed to the expectation from the single dose result, steady state exposures were similar among CYP2C19 phenotypes. These data supported the subsequent global Phase 2 study to permit a low-fat meal around dosing and no dose adjustment for any CYP2C19 phenotype.