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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Effect of ketoconazole on the pharmacokinetics of oral bosutinib in healthy subjects.
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Effect of ketoconazole on the pharmacokinetics of oral bosutinib in healthy subjects.

机译：酮康唑对健康受试者口服博舒替尼药代动力学的影响。

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Bosutinib (SKI-606), a dual inhibitor of Src and Abl tyrosine kinases, is being developed for the treatment of chronic myelogenous leukemia. The effect of coadministration of ketoconazole on the pharmacokinetic (PK) profile of bosutinib was evaluated in an open-label, randomized, 2-period, crossover study. Healthy subjects (fasting) received a single dose of oral bosutinib 100 mg alone and with multiple once-daily doses of oral ketoconazole 400 mg. PK sampling occurred through 96 hours. The least square geometric mean treatment ratios (90% confidence interval [CI]) of C(max(bosutinib+ketoconazole))/C(max(bosutinib alone)), AUC(T(bosutinib+ketoconazole))/AUC(T(bosutinib alone)), and AUC((bosutinib+ketoconazole))/AUC((bosutinib alone)) were assessed. Compared with bosutinib administered alone, coadministration with ketoconazole increased bosutinib C(max) 5.2-fold, AUC(T) 7.6-fold, and AUC 8.6-fold. Ketoconazole coadministration decreased the mean apparent clearance of bosutinib approximately 9-fold and increased the mean (SD) terminal half-life from 46.2 (16.4) hours to 69.0 (29.1) hours. The incidence of adverse events (AEs) was comparable between the 2 treatments. The most common AEs were headache, nausea, and increased blood creatinine. No safety-related discontinuations or serious AEs occurred. These PK results indicate that bosutinib is susceptible to interaction with potent CYP3A4 inhibitors.
机译：Bosutinib（SKI-606）是Src和Abl酪氨酸激酶的双重抑制剂，目前正在开发中，用于治疗慢性粒细胞性白血病。在开放标签，随机，2期，交叉研究中评估了酮康唑共同给药对波舒替尼药代动力学（PK）谱的影响。健康受试者（禁食）单独服用单剂量的口服博舒替尼100 mg，每天服用多次口服酮康唑400 mg。 PK采样持续了96个小时。 C（max（bosutinib + keconconazole））/ C（max（bosutinib单独）），AUC（T（bosutinib + keconconazole））/ AUC（T（分别评估了Bosutinib）和AUC（（bosutinib + ketoconazole））/ AUC（（bosutinib单独））。与单独使用博舒替尼相比，与酮康唑合用可增加博舒替尼C（max）5.2倍，AUC（T）7.6倍和AUC 8.6倍。酮康唑共同给药可将博舒替尼的平均表观清除率降低约9倍，并将平均（SD）终末半衰期从46.2（16.4）小时增加至69.0（29.1）小时。两种疗法的不良事件发生率相当。最常见的AE是头痛，恶心和血肌酐升高。没有发生安全相关的停药或严重的不良事件。这些PK结果表明bosutinib易与有效CYP3A4抑制剂相互作用。

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