The effects of ketoconazole and rifampin on the single-dose pharmacokinetics of crizotinib in healthy subjects
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To investigate the potential effects of strong CYP3A inhibitor ketoconazole and strong CYP3A inducer rifampin on the pharmacokinetics of crizotinib in human.
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.
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.
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.
KeywordsCrizotinib Ketoconazole Rifampin CYP3A Pharmacokinetics
Studies A8081015 and A8081016 were sponsored by Pfizer Inc. Editorial assistance was provided by Joseph Mole at ACUMED® (Tytherington, UK), an Ashfield Company, and was funded by Pfizer Inc. We thank Grace Ni, Suzanne Phillips, and other operational colleagues at Pfizer for their contribution to the conduct of the two studies, Cathie Leister for providing statistical support, and Robert LaBadie at Pfizer for a critical statistical review of the manuscript.
Huiping Xu supervised all stages of the project and contributed to study concept and design, data acquisition and interpretation, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and final approval of the manuscript. Melissa O’Gorman contributed to study design, data analysis and interpretation, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and final approval of the manuscript. Weiwei Tan contributed to study concept and design, data interpretation, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and final approval of the manuscript. Nicoletta Brega contributed to study design, data acquisition and interpretation, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and final approval of the manuscript. Akintunde Bello contributed to study concept and design, data interpretation, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and final approval of the manuscript.
Conflict of interest
All authors were Pfizer employees and held Pfizer stock at the time this study was conducted.
Ethics approval and consent to participate
The study protocols (Study A8081015 [NCT01149785] and Study A8081016 [NCT01147055]) and informed consent documentation were approved by the Aspire Institutional Review Board (La Mesa, CA, USA). The studies were conducted in compliance with the Declaration of Helsinki and all International Conference on Harmonization Good Clinical Practice Guidelines. All local regulatory requirements were followed: in particular, those affording greater protection to the safety of study participants.
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