Bioanalysis of Ibrutinib and its Active Metabolite in Human Plasma: Selectivity Issue, Impact Assessment and Resolution

Abstract

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.

Phase 1 trial of rituximab, lenalidomide, and ibrutinib in previously untreated follicular lymphoma: Alliance A051103

“…The lower limit of quantitation (LLOQ) and the precision (%CV) of the assay in human plasma were 0.5 ng/mL and ,11%, respectively. 12 Pharmacokinetic data analysis. Plasma ibrutinib and PCI-45227 concentration-time profiles were initially inspected on a log-linear plot and analyzed using noncompartmental methods (WinNonLn Pro software).…”

Recent developments in the chromatographic bioanalysis of approved kinase inhibitor drugs in oncology

“…However, the optimization of MRM is rather time consuming and requires a skilled technician, as cross-talk, adducts and non-specific CID-transitions have to be accounted for [119]. Co-eluting matrix-components with a very close m/z value to that of the analyzed parent drug can also be problematic in SRM acquisition [72,120,121]. Due to its selectivity, with SRM acquisition of additional information like degradation products or adducts of the analytes of interest is lost.…”

“…Next to effects on ionization, isobaric interferences can prove problematic as well. Such an example can be taken from the analysis of ibrutinib, where in plasma samples from a clinical study in hepatically impaired subjects, taurocholic acid showed interference with the internal standard of the active metabolite dihydrodiol-ibrutinib [72]. Some TKIs require specific conditions when handling, such as sunitinib, where exposure of the samples to light causes isomerization, and all sample preparation must be done in light-protected conditions [69].…”

“…This frequently led to laborious time consuming methods, which coincidingly often used large amounts of organic solvents. With more selective analytical techniques, such as mass spectrometry, interference plays a substantially smaller role, although isobaric interferences can still occur [72]. In MS detection, the preparative technique still plays a crucial role, as the most frequent used ionization technique is ESI, which is sensitive for ion suppression.…”

“…Most sample preparative methods can be employed on the 96-well format, and the aid of liquid handling robots makes processing the plates even faster, whilst requiring less human operation [91]. Of the reviewed TKI assays, some make use of the format for PP [31,72], SPE [21,92,94] and SLE [91]. The 96-well format provides a universal format for analytical sample preparation, plates can be handled through devices like vacuum or pressurizing systems aiding in the flow through SPE or SLE columns or filters.…”