Evaluation of the effect of modafinil on the pharmacokinetics of encorafenib and binimetinib in patients with BRAF V600-mutant advanced solid tumors.

IF 2.7 4区医学 Q3 ONCOLOGY Cancer Chemotherapy and Pharmacology Pub Date : 2024-09-01 Epub Date: 2024-06-15 DOI:10.1007/s00280-024-04676-2

Joseph Piscitelli, Micaela B Reddy, Lance Wollenberg, Laurence Del Frari, Jason Gong, Kyle Matschke, Jason H Williams

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Abstract

Background: A clinical drug-drug interaction (DDI) study was designed to evaluate the effect of multiple doses of modafinil, a moderate CYP3A4 inducer at a 400 mg QD dose, on the multiple oral dose pharmacokinetics (PK) of encorafenib and its metabolite, LHY746 and binimetinib and its metabolite, AR00426032.

Methods: This study was conducted in patients with BRAF V600-mutant advanced solid tumors. Treatment of 400 mg QD modafinil was given on Day 15 through Day 21. Encorafenib 450 mg QD and binimetinib 45 mg BID were administered starting on Day 1. PK sampling was conducted from 0 to 8 h on Day 14 and Day 21. Exposure parameters were calculated for each patient by noncompartmental analysis and geometric least-squares mean ratio. Corresponding 90% confidence intervals were calculated to estimate the magnitude of effects.

Results: Among 11 PK evaluable patients, encorafenib C_max and AUC_last were decreased in presence of steady-state modafinil by 20.2% and 23.8%, respectively. LHY746 exposures were not substantially changed in the presence of steady-state modafinil.

Conclusion: The results from this clinical study indicate modafinil 400 mg QD had a weak effect on encorafenib PK. Based on these results, encorafenib can be coadministered with a moderate CYP3A4 inducer without dosing adjustment.

Clinical trial registration: ClinicalTrials.gov NCT03864042, registered 6 March 2019.

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评估莫达非尼对 BRAF V600 突变晚期实体瘤患者服用安戈非尼和宾美替尼的药代动力学的影响。

研究背景一项临床药物相互作用（DDI）研究旨在评估多剂量莫达非尼（400 mg QD剂量的中度CYP3A4诱导剂）对安戈非尼及其代谢物LHY746和比尼替尼及其代谢物AR00426032的多剂量口服药代动力学（PK）的影响：本研究以BRAF V600突变晚期实体瘤患者为研究对象。第 15 天至第 21 天给予 400 毫克 QD 莫达非尼治疗。从第1天开始服用安科拉非尼（Encorafenib）450毫克 QD和比尼替尼（binimetinib）45毫克 BID。在第 14 天和第 21 天的 0 至 8 小时进行 PK 采样。通过非室分析和几何最小二乘均值比计算每位患者的暴露参数。计算了相应的 90% 置信区间，以估计效应的大小：在11名可进行PK评估的患者中，安戈非尼的Cmax和AUClast在服用稳态莫达非尼后分别降低了20.2%和23.8%。稳态莫达非尼存在时，LHY746的暴露量没有发生实质性变化：这项临床研究的结果表明，莫达非尼 400 毫克 QD 对安戈非尼的 PK 影响较弱。基于这些结果，安戈非尼可以与中度CYP3A4诱导剂联合用药而无需调整剂量：临床试验注册：ClinicalTrials.gov NCT03864042，2019年3月6日注册。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Chemotherapy and Pharmacology 医学-药学

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.