Bioanalysis of ibrutinib and its active metabolite in human plasma: selectivity issue, impact assessment and resolution

Ronald de Vries graduated in Organic and Analytical Chemistry at the Free University of Amsterdam, The Netherlands. After working in a Contract Laboratory (CRO) for 7 years, he joined Janssen R&D in 1998. At Janssen R&D, Belgium, Ronald worked in the bioanalytical department that supports both clinical and nonclinical bioanalysis. In this department he had several roles, such as providing the bioanalytical support for various drug development programs and leading the method establishment group. He has done numerous global assay transfers to/from Janssen from/to other laboratories and plays an important role in the introduction and application of new technologies and applied innovation in the department. In 2014 he started in the drug metabolism and pharmacokinetics department of Janssen R&D, where his main tasks are in vivo and in vitro metabolite identification using high resolution MS and radiodetection. Ibrutinib is a potent, covalently binding inhibitor of Bruton's tyrosine kinase. Quantitative LC-MS/MS methods for ibrutinib and metabolite dihydrodiol-ibrutinib in human plasma were validated in the range 0.500-100 ng/ml. Selectivity of the assay toward isobaric metabolites and endogenous compounds was optimized and incurred sample reproducibility and stability were assessed. During analysis of plasma samples from a clinical study in hepatically impaired subjects, bile acids, more specifically taurocholic acid, showed interference with the internal standard of dihydrodiol-ibrutinib. This interference was significant in samples from hepatically impaired subjects, but did not impact results from all other clinical studies analyzed. The method was modified and revalidated, and an impact assessment was performed. The original method and the modified method were cross-validated.