卡匹伐他汀在晚期或转移性实体瘤患者中的群体药代动力学。

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Clinical Pharmacokinetics Pub Date : 2024-08-01 Epub Date: 2024-08-10 DOI:10.1007/s40262-024-01407-x
Carlos Fernandez-Teruel, Marie Cullberg, Cath Eberlein, Simon T Barry, Diansong Zhou
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引用次数: 0

摘要

背景和目的:许多癌症都可能发生 PI3K/AKT 通路的过度激活。Capivasertib 是一种强效、选择性的泛 AKT 抑制剂。本分析的目的是为卡非伐他汀建立一个群体药代动力学模型,并定量评估内在和外在因素对卡非伐他汀药代动力学的影响:方法:合并四项I期和II期研究的药代动力学数据。卡匹伐他汀的口服剂量范围为80-800毫克,每天两次,28天和21天为一个周期,作为单药或与紫杉醇或氟维司群联合用药,采用连续给药或两种间歇给药方案之一:开4天,停3天(4/3)或开2天,停5天(2/5)。测试了几种模型和方法描述卡匹伐他汀处置的能力。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、制剂以及同时使用紫杉醇、氟维司群、细胞色素P450家族3A亚家族(CYP3A)诱导剂、CYP3A抑制剂和酸还原剂:结果:共纳入了441名患者的3963个卡非伐他汀血浆浓度。卡伐他汀的药代动力学由一个三室模型充分描述,其表观清除率(CL/F)呈中度时间依赖性和剂量依赖性。口服多剂量卡匹伐替布(400毫克,每天两次;[4/3])后,初始CL/F为62.2升/小时(受试者间变异性为39.3%),约120小时后,CL/F下降了18%。有效半衰期为 8.34 小时。据预测,从第二周开始,每周的第三和第四个用药日将达到稳态,其暴露水平可产生对 AKT 的强力抑制,但对其他相关激酶的抑制作用则不明显。多次给药后,卡匹伐他汀的血浆浓度-时间曲线下面积和最大血浆浓度在80-480毫克的剂量水平之间成正比,但超过480毫克后则不成比例。日程、年龄、种族、性别、肌酐清除率、肝功能、肾功能、吸烟状况以及同时使用氟维司群、CYP3A诱导剂、CYP3A抑制剂或减酸剂对卡匹伐他汀的药代动力学无显著协变量影响。同时使用紫杉醇、食物效应和制剂对卡匹伐他汀的药代动力学有显著的统计学影响,但影响程度较低。体重与卡匹伐他汀的CL/F有显著的统计学关系,体重较轻时(47公斤与67公斤参考值),稳态时的CL/F降低12%,稳态时12小时的曲线下面积增加14%,稳态时的最大浓度增加14%:卡匹伐他汀的药代动力学显示出中等程度的受试者间变异性,评估的大多数协变量没有显著影响。体重、剂量、同时使用紫杉醇、食物效应和制剂在统计学上有显著影响。不过,预计这些因素会通过以下方式影响卡匹伐他汀的暴露量
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Population Pharmacokinetics of Capivasertib in Patients with Advanced or Metastatic Solid Tumours.

Background and objective: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

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来源期刊
CiteScore
8.80
自引率
4.40%
发文量
86
审稿时长
6-12 weeks
期刊介绍: Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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