PI3K/AKT 通路过度激活可能发生在许多癌症中。 Capivasertib 是一种有效的选择性泛 AKT 抑制剂。本分析的目的是开发 capivasertib 的群体药代动力学模型，并定量评估内在和外在因素对 capivasertib 药代动力学的影响。合并了四项 I 期和 II 期研究的药代动力学数据。 Capivasertib 口服给药，剂量范围为 80-800 mg，每天两次，28 天和 21 天的周期内作为单一疗法或与紫杉醇或氟维司群联合使用，使用连续给药或两种间歇给药方案之一：连续 4 天、休息 3 天 (4/3) 或休息 2 天，休息 5 天 (2/5)。测试了几种模型和方法描述 capivasertib 处置的能力。评估的协变量包括剂量、疗程、年龄、体重、种族、性别、肌酐清除率、肝功能、肾功能、吸烟状况、食物影响、制剂以及与紫杉醇、氟维司群、细胞色素P450、家族3、亚家族A的联合使用(CYP3A) 诱导剂、CYP3A 抑制剂和酸还原剂。共纳入了 441 名患者的 3963 个 capivasertib 血浆浓度。 Capivasertib 药代动力学通过三室模型充分描述，其中表观清除率 (CL/F) 呈现中等的时间依赖性和剂量依赖性清除率。口服多次剂量的 capivasertib（400 mg，每日两次；[4/3]）后，初始 CL/F 为 62.2 L/h（受试者间变异性 39.3%），约 120 小时后，CL/F 下降18%。有效半衰期为8.34小时。从第二周开始，预计每周第三和第四个给药日将达到稳定状态，其暴露水平会对 AKT 产生强烈抑制，但不会对其他相关激酶产生强烈抑制。多次给药后，血浆浓度-时间曲线下面积和 capivasertib 的最大血浆浓度在 80-480 mg 剂量水平之间成比例，但超过 480 mg 则比例更大。时间表、年龄、种族、性别、肌酐清除率、肝功能、肾功能、吸烟状况以及与氟维司群、CYP3A诱导剂、CYP3A抑制剂或酸还原剂的合用对于capivasertib药代动力学不具有显着的协变量。紫杉醇、食物效应和制剂的联合使用对capivasertib的药代动力学有统计学上的显着影响，但影响较低。体重与 capivasertib CL/F 具有统计显着相关性，稳态时 CL/F 降低 12%，稳态下 12 小时曲线下面积增加 14%，稳态时最大浓度较低体重（47 kg 与 67 kg 参考值）。Capivasertib 药代动力学显示中等的受试者间变异性，并且评估的大多数协变量没有显着影响。体重、剂量、紫杉醇的联合使用、食物效应和制剂显示出统计学上显着的影响。然而，这些预计会对 capivasertib 暴露的影响<20%，并且预计不具有临床相关性。根据群体药代动力学，无需针对内在和外在因素进行先验剂量调整。© 2024。作者。

Overactivation of the PI3K/AKT pathway can occur in many cancers. Capivasertib is a potent, selective pan-AKT inhibitor. The objectives of this analysis were to develop a population pharmacokinetic model for capivasertib and to quantitatively assess the impact of intrinsic and extrinsic factors on the pharmacokinetics of capivasertib.Pharmacokinetic data from four phase I and II studies were combined. Capivasertib was administered orally at a dose range of 80-800 mg twice daily over 28-day and 21-day cycles as monotherapy or in combination with paclitaxel or fulvestrant, using continuous dosing or one of two intermittent dosing schedules: either 4 days on, 3 days off (4/3) or 2 days on, 5 days off (2/5). Several models and approaches were tested for their ability to describe capivasertib disposition. The covariates assessed included dose, schedule, age, body weight, race, sex, creatinine clearance, hepatic function, renal function, smoking status, food effect, formulation, and concomitant use with paclitaxel, fulvestrant, cytochrome P450, family 3, subfamily A (CYP3A) inducers, CYP3A inhibitors and acid-reducing agents.A total of 3963 capivasertib plasma concentrations from 441 patients were included. Capivasertib pharmacokinetics was adequately described by a three-compartment model where the apparent clearance (CL/F) presented a moderate time-dependent and dose-dependent clearance. Following oral administration of multiple doses of capivasertib (400 mg twice daily; [4/3]), the initial CL/F was 62.2 L/h (between-subject variability 39.3%), and after approximately 120 hours, CL/F decreased by 18%. The effective half-life was 8.34 h. Steady state was predicted to be reached on every third and fourth dosing day each week from the second week with exposure levels that produced robust inhibition of AKT but not of other related kinases. The area under the plasma concentration-time curve and maximum plasma concentration of capivasertib were proportional between the dose levels of 80-480 mg after multiple doses but more than proportional beyond 480 mg. Schedule, age, race, sex, creatinine clearance, hepatic function, renal function, smoking status and concomitant use with fulvestrant, CYP3A inducers, CYP3A inhibitors or acid-reducing agents were not significant covariates for capivasertib pharmacokinetics. Concomitant use of paclitaxel, food effect and formulation statistically significantly affected capivasertib pharmacokinetics, but the effect was low. Body weight was statistically significantly related to capivasertib CL/F, with a 12% reduction in CL/F at steady state and a 14% increase in the area under the curve for 12 hours at steady state and maximum concentration at steady state at a lower body weight (47 kg vs 67 kg reference).Capivasertib pharmacokinetics showed moderate between-subject variability, and most covariates assessed had no significant impact. Body weight, dose, concomitant use of paclitaxel, food effect and formulation showed statistically significant effects. However, these were predicted to impact exposure to capivasertib by  <20% and were not expected to be clinically relevant. Based on the population pharmacokinetics, no a priori dose adjustment is needed for intrinsic and extrinsic factors.© 2024. The Author(s).