The effects of ketoconazole and rifampin on the single-dose pharmacokinetics of crizotinib in healthy subjects.

Objective: To investigate the potential effects of strong CYP3A inhibitor ketoconazole and strong CYP3A inducer rifampin on the pharmacokinetics of crizotinib in human.

Methods: Two separate open-label, 2-period, 2-treatment, 1-sequence, crossover, single-dose studies were conducted in healthy subjects with and without ketoconazole or rifampin. Series of plasma samples were collected after each crizotinib dose to determine concentration of crizotinib and its metabolite PF-06260182. Relevant pharmacokinetic (PK) parameters for crizotinib and PF096269182 were estimated by standard non-compartmental analysis (NCA) method.

Results: Co-administration of a single 150-mg oral dose of crizotinib with the strong CYP3A inhibitor ketoconazole resulted in an area under the plasma-concentration curve extrapolated to infinity (AUC0-inf) 3.2-fold that for crizotinib alone. Co-administration of a single 250-mg crizotinib dose with the strong CYP3A inducer rifampin caused an 82 % decrease in crizotinib AUC0-inf. Respective increases and decreases in systemic exposure to the crizotinib metabolite PF-06260182 following co-administration of ketoconazole and rifampin were greater than those seen for crizotinib.

Conclusions: These findings suggest that CYP3A plays an important role in the metabolism of both crizotinib and PF-06260182, with the extent of this role being greater for PF-06260182. There were no serious adverse events or deaths and no dose reductions or temporary or permanent discontinuations due to drug-related adverse events in either study.