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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Potential Interactions Between HIV Drugs, Ritonavir and Efavirenz and Anticancer Drug, Nilotinib-A Study in Primary Cultures of Human Hepatocytes That Is Applicable to HIV Patients With Cancer
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Potential Interactions Between HIV Drugs, Ritonavir and Efavirenz and Anticancer Drug, Nilotinib-A Study in Primary Cultures of Human Hepatocytes That Is Applicable to HIV Patients With Cancer

机译：HIV药物Ritonavir和Efavirenz与抗癌药物Nilotinib之间的潜在相互作用-适用于患有癌症的HIV患者的人类肝细胞原代培养研究

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Nilotinib is used to treat chronic myeloid leukemia (CML), and is metabolized by CYP3A. With a black-box warning for QT prolongation, which is exposure dependent, controlling for drug interactions is clinically relevant. Treatments of HIV patients with CML are with HAART drugs, ritonavir and efavirenz, may cause complex drug interactions through CYP3A inhibition or induction. We evaluated the interactions of ritonavir or efavirenz on nilotinib using human hepatocytes and compared these interactions with those of ketoconazole or rifampin, classical CYP3A inhibitor and inducer, respectively. Hepatocytes were treated with vehicle, ritonavir (10 M), ketoconazole (10 M), efavirenz (10 M), or rifampin (10 M) for 5 days. On day 5, nilotinib (3 M) was coincubated for an additional 24-48 hours. The concentrations of nilotinib were quantitated in collected samples (combined lysate and medium) by LC-MS. Apparent intrinsic clearance (CLint,app) of nilotinib was lowered 5.8- and 3.1-fold, respectively, by ritonavir and ketoconazole. Efavirenz and rifampin increased the CLint,app of nilotinib by 2.1- and 4.1-fold, respectively. The clinically recommended dose (300 mg twice daily) of nilotinib may have to be reduced substantially (150 mg once daily) or increased (400 mg thrice daily), respectively, to achieve desired drug exposure, when ritonavir or efavirenz is co-administered.
机译：尼洛替尼用于治疗慢性粒细胞白血病（CML），并通过CYP3A代谢。由于QT延长的黑盒警告取决于暴露，因此控制药物相互作用具有临床意义。 HIV感染CML的患者使用HAART药物，利托那韦和依非韦伦治疗，可能通过CYP3A抑制或诱导而引起复杂的药物相互作用。我们使用人肝细胞评估了利托那韦或依法韦仑对尼罗替尼的相互作用，并将这些相互作用分别与酮康唑或利福平，经典CYP3A抑制剂和诱导剂进行了比较。肝细胞用媒介物，利托那韦（10 M），酮康唑（10 M），依非韦伦（10 M）或利福平（10 M）处理5天。在第5天，尼洛替尼（3 M）再孵育24至48小时。通过LC-MS对收集的样品（裂解物和培养基的组合）中尼罗替尼的浓度进行定量。利托那韦和酮康唑分别将尼洛替尼的表观固有清除率（CLint，app）降低了5.8倍和3.1倍。依法韦仑和利福平分别使尼洛替尼的CLint，app提高了2.1倍和4.1倍。当联合使用利托那韦或依法韦仑时，尼洛替尼的临床推荐剂量（每天两次300 mg）必须分别大幅减少（每天一次150 mg）或增加（每天三次400 mg）以达到所需的药物暴露。

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