Effects of Renal Function on Crizotinib Pharmacokinetics: Dose Recommendations for Patients with ALK-Positive Non-Small Cell Lung Cancer.

Abstract

Crizotinib (250mg 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 250mg once daily.