安可拉非尼对布洛芬、瑞舒伐他汀和铜卟啉 I 影响的临床评估以及他汀类药物联合用药的注意事项。

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Clinical Pharmacokinetics Pub Date : 2024-04-01 Epub Date: 2024-02-29 DOI:10.1007/s40262-024-01352-9
Joseph Piscitelli, Micaela B Reddy, Lance Wollenberg, Laurence Del Frari, Jason Gong, Linda Wood, Yizhong Zhang, Kyle Matschke, Jason H Williams
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引用次数: 0

摘要

背景和目的安科拉非尼是一种激酶抑制剂,分别用于治疗具有特定BRAF V600突变的不可切除或转移性黑色素瘤或转移性结直肠癌患者。一项临床药物相互作用(DDI)研究旨在评估安戈非尼对罗伐他汀(OATP1B1/3和乳腺癌抗性蛋白(BCRP)的敏感底物)和安非他酮(CYP2B6的敏感底物)的影响。在另一项研究中测定了OATP1B1的内源性底物--铜卟啉I(CP-I),以揭示转运体DDI的机制:DDI研究参与者分别在第7、1和14天口服单剂量罗伐他汀(10毫克)和安非他酮(75毫克),并从第1天开始连续口服安戈非尼(450毫克 QD)和替米替尼(45毫克 BID)。CP-I数据是从接受安戈非尼(300 毫克 QD)和西妥昔单抗(400 毫克/平方米初始剂量,然后 250 毫克/平方米 QW)治疗的 3 期研究参与者中收集的。药代动力学和药效学分析采用非室和室方法进行:结果:安戈非尼和比尼美替尼重复给药后,布洛芬的暴露量没有增加,而罗伐他汀的Cmax和接收器工作特征曲线下面积(AUC)分别增加了约2.7倍和1.6倍。CP-I的增加很小,这表明安戈非尼对罗伐他汀的主要影响是通过BCRP产生的。根据他汀类药物的代谢和转运特征对其进行分类,表明普伐他汀与安戈非尼合用时发生相互作用的可能性最小:这些临床研究结果表明,安戈非尼不会引起临床相关的CYP2B6诱导或抑制,但它是BCRP的抑制剂,也可能在较小程度上抑制OATP1B1/3。基于这些结果,在与安戈非尼联合用药时可能需要考虑更换他汀类药物或相应减少他汀类药物的剂量:临床试验注册:ClinicalTrials.gov NCT03864042,2019年3月6日注册。
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Clinical Evaluation of the Effect of Encorafenib on Bupropion, Rosuvastatin, and Coproporphyrin I and Considerations for Statin Coadministration.

Background and objectives: Encorafenib is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma or metastatic colorectal cancer, respectively, with selected BRAF V600 mutations. A clinical drug-drug interaction (DDI) study was designed to evaluate the effect of encorafenib on rosuvastatin, a sensitive substrate of OATP1B1/3 and breast cancer resistance protein (BCRP), and bupropion, a sensitive CYP2B6 substrate. Coproporphyrin I (CP-I), an endogenous substrate for OATP1B1, was measured in a separate study to deconvolute the mechanism of transporter DDI.

Methods: DDI study participants received a single oral dose of rosuvastatin (10 mg) and bupropion (75 mg) on days - 7, 1, and 14 and continuous doses of encorafenib (450 mg QD) and binimetinib (45 mg BID) starting on day 1. The CP-I data were collected from participants in a phase 3 study who received encorafenib (300 mg QD) and cetuximab (400 mg/m2 initial dose, then 250 mg/m2 QW). Pharmacokinetic and pharmacodynamic analysis was performed using noncompartmental and compartmental methods.

Results: Bupropion exposure was not increased, whereas rosuvastatin Cmax and area under the receiver operating characteristic curve (AUC) increased approximately 2.7 and 1.6-fold, respectively, following repeated doses of encorafenib and binimetinib. Increase in CP-I was minimal, suggesting that the primary effect of encorafenib on rosuvastatin is through BCRP. Categorization of statins on the basis of their metabolic and transporter profile suggests pravastatin would have the least potential for interaction when coadministered with encorafenib.

Conclusion: The results from these clinical studies suggest that encorafenib does not cause clinically relevant CYP2B6 induction or inhibition but is an inhibitor of BCRP and may also inhibit OATP1B1/3 to a lesser extent. Based on these results, it may be necessary to consider switching statins or reducing statin dosage accordingly for coadministration with encorafenib.

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

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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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