Purpose: This metabolite profiling and identification analysis (part of a phase I absorption, distribution, metabolism, and excretion study) aimed to define biotransformation pathways and evaluate associated inter-individual variability in four patients with advanced solid tumors who received [14C]-ixazomib.
Methods: After administration of a single 4.1-mg oral dose of [14C]-ixazomib (total radioactivity [TRA] ~ 500 nCi), plasma (at selected timepoints), urine, and fecal samples were collected before dosing and continuously over 0-168-h postdose, followed by intermittent collections on days 14, 21, 28, and 35. TRA analysis and metabolite profiling were performed using accelerator mass spectrometry. Radiolabeled metabolites were identified using liquid chromatography/tandem mass spectrometry.
Results: Metabolite profiles were similar in plasma, urine, and feces samples across the four patients analyzed. All metabolites identified were de-boronated. In AUC0-816 h time-proportional pooled plasma, ixazomib (54.2% of plasma TRA) and metabolites M1 (18.9%), M3 (10.6%), and M2 (7.91%), were the primary components identified. M1 was the major metabolite, contributing to 31.1% of the 76.2% of the total dose excreted in urine and feces over 0-35-day postdose. As none of the identified metabolites had a boronic acid moiety, they are unlikely to be pharmacologically active.
Conclusions: Hydrolytic metabolism in conjunction with oxidative deboronation appears to be the principal process in the in vivo biotransformation pathways of ixazomib. The inference of formation-rate-limited clearance of ixazomib metabolites and the inferred lack of pharmacologic activity of identified circulating metabolites provides justification for use of parent drug concentrations/systemic exposure in clinical pharmacology analyses.
Keywords: Accelerator mass spectrometry; Biotransformation; Boronic acid; Ixazomib; Phase I.