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Abstract：
OBJECTIVE: 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.
CONCLUSIONS: 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.
BACKGROUND: ClinicalTrials.gov NCT03864042, registered 6 March 2019.
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.
CONCLUSIONS: 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.
BACKGROUND: ClinicalTrials.gov NCT03864042, registered 6 March 2019.
摘要：
目的：恩科拉非尼是一种激酶抑制剂，适用于不可切除或转移性黑色素瘤或转移性结直肠癌患者的治疗，分别,选择BRAFV600突变。一项临床药物-药物相互作用（DDI）研究旨在评估恩科拉非尼对瑞舒伐他汀，OATP1B1/3和乳腺癌耐药蛋白（BCRP）的敏感底物，还有安非他酮,一种敏感的CYP2B6底物。卟啉I（CP-I），在另一项研究中测量了OATP1B1的内源性底物，以对转运蛋白DDI的机制进行去卷积。
方法：DDI研究参与者在第7、1和14天接受单一剂量的瑞舒伐他汀（10mg）和安非他酮（75mg），并在第1天开始连续剂量的恩科非尼（450mgQD）和比尼（45mgBID）。CP-I数据是从接受恩科拉非尼（300mgQD）和西妥昔单抗（400mg/m2初始剂量，然后250mg/m2QW)。使用非房室和房室方法进行药代动力学和药效学分析。
结果：安非他酮暴露量没有增加，而瑞舒伐他汀Cmax和受试者工作特征曲线下面积（AUC）增加约2.7和1.6倍，分别,重复服用恩科拉菲尼和比尼美替尼。CP-I的增加很小，提示恩可拉非尼对瑞舒伐他汀的主要作用是通过BCRP。根据他汀类药物的代谢和转运蛋白谱对其进行分类表明，普伐他汀与恩可拉非尼联合给药时，相互作用的可能性最小。
结论：这些临床研究的结果表明，恩可拉非尼不会引起临床相关的CYP2B6诱导或抑制，而是一种BCRP抑制剂，也可能在较小程度上抑制OATP1B1/3。基于这些结果,可能有必要考虑转换他汀类药物或相应减少他汀类药物的剂量与恩可拉非尼联合给药.
背景：ClinicalTrials.govNCT03864042，注册于2019年3月6日。
方法：DDI研究参与者在第7、1和14天接受单一剂量的瑞舒伐他汀（10mg）和安非他酮（75mg），并在第1天开始连续剂量的恩科非尼（450mgQD）和比尼（45mgBID）。CP-I数据是从接受恩科拉非尼（300mgQD）和西妥昔单抗（400mg/m2初始剂量，然后250mg/m2QW)。使用非房室和房室方法进行药代动力学和药效学分析。
结果：安非他酮暴露量没有增加，而瑞舒伐他汀Cmax和受试者工作特征曲线下面积（AUC）增加约2.7和1.6倍，分别,重复服用恩科拉菲尼和比尼美替尼。CP-I的增加很小，提示恩可拉非尼对瑞舒伐他汀的主要作用是通过BCRP。根据他汀类药物的代谢和转运蛋白谱对其进行分类表明，普伐他汀与恩可拉非尼联合给药时，相互作用的可能性最小。
结论：这些临床研究的结果表明，恩可拉非尼不会引起临床相关的CYP2B6诱导或抑制，而是一种BCRP抑制剂，也可能在较小程度上抑制OATP1B1/3。基于这些结果,可能有必要考虑转换他汀类药物或相应减少他汀类药物的剂量与恩可拉非尼联合给药.
背景：ClinicalTrials.govNCT03864042，注册于2019年3月6日。
