Impact of Interindividual Variability in CYP3A Activity on Ibrutinib and Venetoclax Metabolism In Vitro

Abstract

Ibrutinib and venetoclax are orally administered active agents approved for the treatment of chronic lymphocytic leukemia (CLL), the most common form of adult leukemia in the Western world. Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), whereas venetoclax is a B‐cell lymphoma 2 (BCL2) inhibitor. Although these drugs are effective in CLL treatment, managing life‐threatening side effects remains a clinical challenge. Previous studies have shown that ibrutinib and venetoclax are primarily metabolized by cytochrome P450 (CYP) 3A4. However, the influence of interindividual variation in CYP3A activity on the metabolism of ibrutinib and venetoclax has not been addressed. The objectives of this study were to 1) examine ibrutinib and venetoclax metabolism in single‐donor human liver microsomes and cryopreserved human hepatocytes, and 2) assess the correlation between metabolite formation and CYP3A activity markers. Ibrutinib (5 μM) or venetoclax (2.5 μM) were incubated with human liver microsomes from 20 individual donors. Relative levels of ibrutinib metabolites (PCI45227 and PCI45752) and venetoclax metabolites (M5, M4, and M3) were measured by LC‐MS/MS analysis. Formation of metabolites varied widely between the donors. Metabolite formation was highly correlated with CYP3A activity, as measured by midazolam 1’‐hydroxylation. Pearson correlation coefficients (r) for PCI45227, PCI45752, M5, M4, and M3 were 0.97, 0.85, 0.92, 0.93, and 0.95, respectively. These findings indicate that CYP3A phenotype may have a significant influence on the pharmacokinetics of ibrutinib and venetoclax in CLL treatment. Future studies will be conducted in human hepatocytes to evaluate the effect of CYP3A activity and protein levels on ibrutinib and venetoclax metabolism.