Eli Lilly and Company, Indianapolis, Indiana, USA.
Covance Early Clinical Development, Madison, Wisconsin, USA.
Clin Transl Sci. 2023 Sep;16(9):1617-1627. doi: 10.1111/cts.13573. Epub 2023 Jul 4.
Abemaciclib is an orally administered, potent, and selective small molecule inhibitor of cyclin-dependent kinases 4 and 6, approved for advanced or metastatic breast cancer. This study aimed to use an exposure-response approach to investigate the effect of abemaciclib and its active metabolites (M2 and M20) on QTc interval and delay in cardiac repolarization at clinically relevant exposures. This was a single-blind, randomized, and placebo-controlled study of ascending doses of abemaciclib. Thirty-five healthy participants were administered a single dose of 200-600 mg abemaciclib. Twelve-lead electrocardiogram tracings and pharmacokinetic samples were collected serially pre- and post-dose. The primary objective was to study the relationship between abemaciclib and its active metabolites (M2 and M20) and QTc interval following ascending oral doses of abemaciclib. The secondary objective included evaluating the safety and tolerability of single ascending doses of abemaciclib in healthy participants. Exposure-response analysis demonstrated that there was no significant relationship between placebo-corrected change from baseline QTcF (ΔΔQTcF), abemaciclib, and metabolite plasma concentrations. Additionally, the ΔΔQTcF slopes of abemaciclib, its metabolites, and total analyte concentrations were not statistically different from zero. Single doses of abemaciclib, up to 400 mg, were well-tolerated by healthy participants; however, at the 600 mg dose (three times the highest registered dose), the frequency and severity of treatment-related gastrointestinal events (primarily diarrhea, nausea, and vomiting) increased. In conclusion, single doses of abemaciclib, up to 400 mg, had no statistically or clinically relevant effects on QTc, and abemaciclib was well tolerated up to a dose of 400 mg in this study.
阿贝西利是一种口服的、有效的、选择性的细胞周期蛋白依赖性激酶 4 和 6 小分子抑制剂，用于治疗晚期或转移性乳腺癌。本研究旨在采用暴露-反应方法，研究阿贝西利及其活性代谢物（M2 和 M20）在临床相关暴露水平下对 QTc 间期和心脏复极延迟的影响。这是一项阿贝西利递增剂量的单盲、随机、安慰剂对照研究。35 名健康参与者单次服用 200-600mg 阿贝西利。给药前后连续采集 12 导联心电图和药代动力学样本。主要目的是研究阿贝西利及其活性代谢物（M2 和 M20）与阿贝西利递增口服剂量后 QTc 间期的关系。次要目的包括评估健康参与者单次递增剂量阿贝西利的安全性和耐受性。暴露-反应分析表明，阿贝西利和代谢物血浆浓度与校正后基线 QTcF（ΔΔQTcF）的变化之间没有显著关系。此外，阿贝西利、其代谢物和总分析物浓度的 ΔΔQTcF 斜率与零没有统计学差异。健康参与者耐受高达 400mg 的单剂量阿贝西利；然而，在 600mg 剂量（三倍于最高注册剂量）时，治疗相关胃肠道事件（主要是腹泻、恶心和呕吐）的频率和严重程度增加。总之，单剂量的阿贝西利，高达 400mg，对 QTc 没有统计学或临床相关影响，在这项研究中，阿贝西利在高达 400mg 的剂量下耐受性良好。
