Pharmacokinetic (PK) drug interaction studies of cabozantinib: Effect of CYP3A inducer rifampin and inhibitor ketoconazole on cabozantinib plasma PK and effect of cabozantinib on CYP2C8 probe substrate rosiglitazone plasma PK
Pharmacokinetic (PK) drug interaction studies of cabozantinib: Effect of CYP3A inducer rifampin and inhibitor ketoconazole on cabozantinib plasma PK and effect of cabozantinib on CYP2C8 probe substrate rosiglitazone plasma PK
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DOI：
10.1002/jcph.510
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发表时间：
2015-09-01
影响因子：
2.9
通讯作者：
Lacy, Steven
中科院分区：
文献类型：
--
作者：
Linh Nguyen;Holland, Jaymes;Lacy, Steven
卡博替尼是一种小分子酪氨酸激酶抑制剂，已被批准用于治疗进行性转移性甲状腺髓样癌患者。体外数据表明，（1）细胞色素P450（CYP）3A 4是参与卡博替尼代谢的主要CYP同工酶，（2）CYP 2C 8是卡博替尼最有效抑制的CYP同工酶，在临床相关血浆暴露下具有体内抑制潜力。在临床上评价了卡博替尼与（1）健康志愿者中的CYP 3A诱导剂（利福平）、（2）健康志愿者中的CYP 3A抑制剂（酮康唑）和（3）实体瘤患者中的CYP 2C 8底物（罗格列酮）之间的药代动力学（PK）药物-药物相互作用（DDI）。与单独给予的卡博替尼相比，与利福平共同给药导致卡博替尼的血浆清除率（CL/F）高4.3倍，卡博替尼血浆AUC（0-inf）降低77%，而与酮康唑共同给药使卡博替尼CL/F降低29%，卡博替尼AUC（0-inf）增加38%。与卡博替尼长期共同给药对罗格列酮血浆C-max、AUC（0-24）或AUC（0-inf）无显著影响。总之，当给予卡博替尼时，应避免长期使用强CYP 3A诱导剂和抑制剂，并且预期临床相关暴露的卡博替尼不会通过抑制CYP 3A酶显著影响伴随药物的PK。
Cabozantinib is a small-molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. In vitro data indicate that (1) cytochrome P450 (CYP) 3A4 is the primary CYP isoenzyme involved in the metabolism of cabozantinib, and (2) CYP2C8 is the CYP isoenzyme most potently inhibited by cabozantinib with potential for in vivo inhibition at clinically relevant plasma exposures. Pharmacokinetic (PK) drug-drug interactions (DDIs) were evaluated clinically between cabozantinib and (1) a CYP3A inducer (rifampin) in healthy volunteers, (2) a CYP3A inhibitor (ketoconazole) in healthy volunteers, and (3) a CYP2C8 substrate (rosiglitazone) in patients with solid tumors. Compared with cabozantinib given alone, coadministration with rifampin resulted in a 4.3-fold higher plasma clearance (CL/F) of cabozantinib and a 77% decrease in cabozantinib plasma AUC(0-inf), whereas coadministration with ketoconazole decreased cabozantinib CL/F by 29% and increased cabozantinib AUC(0-inf) by 38%. Chronic coadministration with cabozantinib resulted in no significant effect on rosiglitazone plasma C-max, AUC(0-24), or AUC(0-inf). In summary, chronic use of strong CYP3A inducers and inhibitors should be avoided when cabozantinib is administered, and cabozantinib at clinically relevant exposures is not anticipated to markedly affect the PK of concomitant medications via CYP enzyme inhibition.