Clinical implications of an analysis of pharmacokinetics of crizotinib coadministered with dexamethasone in patients with non-small cell lung cancer

Abstract

Dexamethasone is a systemic corticosteroid and a known cytochrome P450 (CYP)3A inducer. Crizotinib is a selective tyrosine kinase inhibitor of ALK, ROS1, and MET and a substrate of CYP3A. This post hoc analysis characterized the use of concomitant CYP3A inducers with crizotinib and estimated the effect of dexamethasone use on crizotinib pharmacokinetics at steady state. This analysis used data from four clinical studies (PROFILE 1001, 1005, 1007, and 1014) including 1690 patients with non-small cell lung cancer with ALK or ROS1 rearrangements treated with crizotinib at 250mg twice daily. Frequency and reasons for use of concomitant CYP3A inducers, including dexamethasone, with crizotinib were characterized. Multiple steady-state trough concentrations (Ctrough,ss) of crizotinib were measured for each patient. A linear mixed-effects model was used for within-patient comparison of crizotinib Ctrough,ss between dosing of crizotinib alone and crizotinib coadministered with dexamethasone consecutively for ≥ 21days. Dexamethasone was the most commonly used CYP3A inducer (30.4%). A total of 15 patients had crizotinib Ctrough,ss for both crizotinib dosing with and without dexamethasone. The adjusted geometric mean ratio of crizotinib Ctrough,ss following coadministration with dexamethasone relative to crizotinib without dexamethasone, as a percentage, was 98.2% (90% confidence interval, 79.1-122.0%). Crizotinib plasma exposure following coadministration with dexamethasone was similar to that when crizotinib was administered without dexamethasone, indicating dexamethasone has no effect on crizotinib exposure or efficacy. Other CYP3A inducers with similar potency would likewise have no clinically relevant effect on crizotinib exposure.