Modulation of CYP3A Activity to Increase the Oral Bioavailability of Ibrutinib

Abstract

BackgroundIbrutinib (Imbruvica; PCI‐32765), an orally administered inhibitor of Bruton’s tyrosine kinase, is considered a breakthrough targeted therapy that is approved as frontline therapy in chronic lymphocytic leukemia (CLL). Ibrutinib has an average oral bioavailability in humans of <4% with substantial variability in exposure, which predisposes patients to unpredictable and potentially harmful adverse events such as bleeding and atrial fibrillation. As ibrutinib is subject to extensive first‐pass metabolism by CYP3A following oral administration, inhibition of CYP3A activity may be a promising strategy to increase the bioavailability and decrease inter‐individual pharmacokinetic (PK) variability of ibrutinib. The objective of this study was to characterize the impact of CYP3A on the PK of ibrutinib and its main active metabolite, PCI‐45227, in mice.MethodsTo characterize the impact of CYP3A on ibrutinib disposition, in vivo PK studies were performed in wild‐type (WT) male and female FVB mice treated with CYP3A inhibitors including ketoconazole (50 mg/kg p.o.) and cobicistat (30 mg/kg; p.o.) or the respective vehicle controls (PEG400 or corn oil p.o.) thirty minutes prior to dosing with ibrutinib (10 mg/kg p.o.). Based on these results, CYP3A(−/−) female FVB mice were treated with ibrutinib (10 mg/kg p.o. or 1 mg/kg i.v.) alone or thirty minutes after administration of cobicistat (30 mg/kg; p.o.). Concentrations of ibrutinib and PCI‐45227 in plasma were determined by a validated method based on liquid chromatography‐tandem mass spectrometry, and PK parameter estimates were calculated with the software package Phoenix WinNonlin (Version 8.1). Student t‐tests comparing mean AUC values between groups were used to determine significance.ResultsThe peak plasma concentration (Cmax) and area under the concentration‐time curve (AUC) of ibrutinib were ~10‐fold higher in mice administered pharmacologic CYP3A inhibitors prior to ibrutinib (P < 0.0001) with a substantial decrease in the PCI‐45227 to ibrutinib AUC ratio. As expected, when ibrutinib was administered orally to CYP3A(−/−) mice, the AUC of ibrutinib in CYP3A(−/−) mice was increased ~10‐fold (P < 0.0001) with almost no formation of the PCI‐45227 metabolite compared with WT mice. Cobicistat did not impact ibrutinib AUC in CYP3A(−/−) mice (P > 0.9), which suggests that CYP3A inhibition is the major mechanism for cobicistat‐induced increases in ibrutinib exposure.ConclusionsPreviously obtained data with other kinase inhibitors indicate that patients with high CYP3A4 activity may benefit from an increased dose to achieve drug concentrations required to interact with kinase targets; a strategy by which enzyme activity is inhibited could achieve similar results. In view of the established inverse‐correlation between absolute bioavailability and inter‐individual PK variability, the current data provide a rationale for the development of exploratory clinical studies aimed at decreasing the variability in ibrutinib exposure by concomitant administration of CYP3A4 inhibitors. Future preclinical efficacy studies will determine the impact of this strategy on survival in mouse models of B‐cell malignancies.