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Modulation of CYP3A Activity to Increase the Oral Bioavailability of Ibrutinib

Ibrutinib (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.