Pharmacokinetic study of capivasertib and the CYP3A4 substrate midazolam in patients with advanced solid tumors

IF 2.7 4区 医学 Q3 ONCOLOGY Cancer Chemotherapy and Pharmacology Pub Date : 2024-04-20 DOI:10.1007/s00280-024-04667-3
Claire Miller, Roberto Sommavilla, Cindy L. O’Bryant, Minal Barve, Afshin Dowlati, Jason J. Luke, Mahmuda Khatun, Thomas Morris, Marie Cullberg
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Abstract

Purpose

Capivasertib, a potent, selective inhibitor of all three AKT serine/threonine kinase (AKT) isoforms, is being evaluated in phase 3 trials in advanced breast and prostate cancer. This study evaluated the drug–drug interaction risk of capivasertib with the cytochrome P450 3A substrate midazolam in previously treated adults with advanced solid tumors.

Methods

Patients received oral capivasertib 400 mg twice daily (BID) on an intermittent schedule (4 days on/3 days off) starting on day 2 of cycle 1 (29 days) and on day 1 of each 28-day cycle thereafter. In cycle 1 only, patients received oral midazolam (1 mg) on day 1 (alone), and days 8 and 12 (3rd day off and 4th day on capivasertib, respectively). Midazolam pharmacokinetics on days 8 and 12 were analyzed versus day 1. Capivasertib, with or without standard-of-care treatment, was continued in patients deemed likely to benefit. Safety and exploratory efficacy analyses were conducted.

Results

Capivasertib–midazolam coadministration increased midazolam exposure (n = 21): geometric mean ratio (90% confidence interval) AUCinf and Cmax was 1.13 (0.97–1.32) and 1.15 (0.99–1.33) for day 8 versus day 1, and 1.75 (1.50–2.05) and 1.25 (1.08–1.46) for day 12 versus day 1. The capivasertib safety profile was manageable when administered with or without midazolam. Two patients had partial responses to treatment.

Conclusion

The up to 1.75-fold increase in midazolam exposure indicates capivasertib is a weak CYP3A inhibitor at 400 mg BID on an intermittent schedule. Capivasertib was well tolerated; exploratory efficacy analysis demonstrated evidence of clinical activity in this heavily pre-treated population.

ClinicalTrials.gov: NCT04958226.

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晚期实体瘤患者服用卡匹伐替和 CYP3A4 底物咪达唑仑的药代动力学研究
目的 卡匹伐他替(capivasertib)是一种对所有三种AKT丝氨酸/苏氨酸激酶(AKT)同工酶都有效的选择性抑制剂,目前正在晚期乳腺癌和前列腺癌的3期试验中进行评估。本研究评估了卡非伐他汀与细胞色素P450 3A底物咪达唑仑在既往接受过治疗的晚期实体瘤成人患者中的药物相互作用风险。方法患者从第1周期(29天)的第2天开始,在此后每个28天周期的第1天按间歇计划(开4天/关3天)口服卡非伐他汀400毫克,每天两次(BID)。仅在第1周期,患者在第1天(单独用药)、第8天和第12天(分别为服用卡匹伐他汀的第3天和第4天)口服咪达唑仑(1毫克)。第 8 天和第 12 天的咪达唑仑药代动力学与第 1 天进行了对比分析。认为可能获益的患者可继续接受卡匹伐他汀治疗或不接受标准护理治疗。结果卡匹伐他汀与咪达唑仑联合用药增加了咪达唑仑的暴露量(n = 21):第8天与第1天相比,AUCinf和Cmax的几何平均比值(90%置信区间)分别为1.13(0.97-1.32)和1.15(0.99-1.33);第12天与第1天相比,分别为1.75(1.50-2.05)和1.25(1.08-1.46)。在使用或不使用咪达唑仑的情况下,卡匹伐他汀的安全性是可控的。结论:咪达唑仑的暴露量增加了1.75倍,这表明卡匹伐他汀是一种弱CYP3A抑制剂,间歇给药400毫克,每日一次。Capivasertib的耐受性良好;探索性疗效分析表明,在这种重度预处理人群中,Capivasertib具有临床活性:NCT04958226。
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来源期刊
CiteScore
6.10
自引率
3.30%
发文量
116
审稿时长
2.5 months
期刊介绍: Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
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