Tan Weiwei, Yamazaki Shinji, Johnson Theodore R, Wang Rong, O'Gorman Melissa T, Kirkovsky Leonid, Boutros Tanya, Brega Nicoletta M, Bello Akintunde
Pfizer Inc, 10646 Science Center Drive, CB10, San Diego, CA, 92121, USA.
Pfizer Inc, Groton, CT, USA.
Clin Drug Investig. 2017 Apr;37(4):363-373. doi: 10.1007/s40261-016-0490-z.
Crizotinib (250 mg twice daily) is the first anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of ALK-positive non-small-cell lung cancer (NSCLC). The objectives of the current study were to evaluate the effects of mild, moderate, and severe renal impairment on crizotinib pharmacokinetics and to make crizotinib dosing recommendations for ALK-positive NSCLC patients with renal impairment on the basis of the findings.
The effects of varying degrees of renal impairment on crizotinib pharmacokinetics were evaluated by: (1) analysis of mild and moderate renal impairment on multiple-dose pharmacokinetics of crizotinib in ALK-positive NSCLC patients from the PROFILE 1001 and PROFILE 1005 trials; (2) analysis of severe renal impairment on single-dose pharmacokinetics of crizotinib in volunteers (Study 1020); and (3) prediction of the effect of severe renal impairment on multiple-dose crizotinib pharmacokinetics using a physiologically-based pharmacokinetic model of crizotinib.
No clinically relevant changes in plasma crizotinib exposure were observed in NSCLC patients with mild or moderate renal impairment. After a single 250-mg dose, the area under the plasma concentration-time curve (AUC) for crizotinib was 1.8-fold greater in subjects with severe renal impairment than in those with normal renal function. Physiologically-based pharmacokinetic modeling indicated a similar increase in steady-state AUC after multiple dosing.
These results suggest no dose adjustment for patients with mild or moderate renal impairment. The recommended crizotinib dose for patients with severe renal impairment not requiring dialysis is 250 mg once daily.
克唑替尼（每日两次，每次250mg）是首个被批准用于治疗间变性淋巴瘤激酶（ALK）阳性非小细胞肺癌（NSCLC）的ALK抑制剂。本研究的目的是评估轻度、中度和重度肾功能损害对克唑替尼药代动力学的影响，并根据研究结果为肾功能损害的ALK阳性NSCLC患者制定克唑替尼给药建议。
通过以下方式评估不同程度肾功能损害对克唑替尼药代动力学的影响：（1）分析PROFILE 1001和PROFILE 1005试验中ALK阳性NSCLC患者轻度和中度肾功能损害对克唑替尼多剂量药代动力学的影响；（2）分析志愿者中重度肾功能损害对克唑替尼单剂量药代动力学的影响（研究1020）；（3）使用基于生理学的克唑替尼药代动力学模型预测重度肾功能损害对克唑替尼多剂量药代动力学的影响。
轻度或中度肾功能损害的NSCLC患者血浆中克唑替尼的暴露量未观察到临床相关变化。单次服用250mg剂量后，重度肾功能损害患者的克唑替尼血浆浓度-时间曲线下面积（AUC）比肾功能正常的患者高1.8倍。基于生理学的药代动力学模型表明多次给药后稳态AUC有类似增加。
这些结果表明轻度或中度肾功能损害患者无需调整剂量。对于不需要透析的重度肾功能损害患者，推荐的克唑替尼剂量为每日一次250mg。
