Eli Lilly and Company, Erl Wood Manor, Windlesham Surrey, GU20 6PH, UK.
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA.
Cancer Chemother Pharmacol. 2019 Mar;83(3):483-492. doi: 10.1007/s00280-018-3750-1. Epub 2018 Dec 11.
Crenigacestat (LY3039478) is a Notch inhibitor currently being investigated in advanced cancer patients. Conducting clinical pharmacology studies in healthy subjects avoids nonbeneficial drug exposures in cancer patients and mitigates confounding effects of disease state and concomitant medications.
Three studies were conducted in healthy subjects, assessing safety, pharmacokinetics, effect on QT interval, and relative and absolute bioavailability of crenigacestat. Crenigacestat was administered as single 25, 50, or 75 mg oral doses or as an intravenous dose of 350 µg CNH-crenigacestat. Electrocardiogram measurements, and plasma and urine samples were collected up to 48 h postdose, and safety assessments were conducted up to 14 days postdose.
Exposures were dose proportional in the 25 to 75 mg dose range and mean elimination half-life was approximately 5-6 h. The exposure achieved from the new formulated capsule was approximately 30% and 20% higher for area under the plasma concentration time curve from time zero to infinity [AUC(0-∞)] and maximum plasma concentration (C), respectively, compared to the reference drug in capsule formulation. The geometric least-squares mean [90% confidence interval (CI)] absolute bioavailability of crenigacestat was 0.572 (0.532, 0.615). The regression slope (90% CI) of placebo-adjusted QTcF against crenigacestat plasma concentration was - 0.001 (- 0.006, 0.003), suggesting no significant linear association. Thirty-nine subjects completed the studies and the majority of adverse events were mild. Single oral doses of 25 to 75 mg crenigacestat and an IV dose of 350 µg CNH-crenigacestat were well tolerated in healthy subjects.
Crenigacestat（LY3039478）是一种 Notch 抑制剂，目前正在晚期癌症患者中进行研究。在健康受试者中进行临床药理学研究可避免癌症患者非有益药物暴露，并减轻疾病状态和伴随药物的混杂影响。
在健康受试者中进行了三项研究，评估了 crenigacestat 的安全性、药代动力学、对 QT 间期的影响以及相对和绝对生物利用度。crenigacestat 以单次 25、50 或 75mg 口服剂量或 350μg CNH-crenigacestat 静脉剂量给药。在给药后 48 小时内采集心电图测量值和血浆及尿液样本，并在给药后 14 天内进行安全性评估。
在 25 至 75mg 剂量范围内，暴露量与剂量成正比，平均消除半衰期约为 5-6 小时。与胶囊制剂中的参比药物相比，新配方胶囊的 AUC（0-∞）和 Cmax 的暴露量分别约高 30%和 20%。crenigacestat 的几何均数（90%置信区间）绝对生物利用度为 0.572（0.532，0.615）。crenigacestat 血浆浓度与安慰剂校正后 QTcF 的回归斜率（90%置信区间）为-0.001（-0.006，0.003），提示无显著线性关联。39 名受试者完成了这些研究，大多数不良事件为轻度。健康受试者单次口服 25 至 75mg crenigacestat 和静脉注射 350μg CNH-crenigacestat 均耐受良好。
