Abstract
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.
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Reproduced from Gupta et al. [8] under the Creative Commons license: https://creativecommons.org/licenses/by-nc/4.0/legalcode
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Acknowledgements
The authors thank all patients and their families, as well as all physicians, nurses, study coordinators, and study center staff for participating in the studies that contributed data for this analysis. The authors also acknowledge Fiona Scott and Laura Webb, of FireKite, an Ashfield company, part of UDG Healthcare plc, who provided medical writing assistance, which was funded by Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; and Renda Ferrari, PhD, of Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, for editorial support.
Funding
This study was funded by Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
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SP, MP, NG, MH, KV, J-TW, CX, XZ, and SC are employees of Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
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Informed consent was obtained from all individual participants included in the study. This study complied with Good Publication Practice 3 ethical guidelines (Battisti WP et al. Ann Intern Med. 2015;163:461–464), the Declaration of Helsinki, and the International Conference on Harmonization Guideline for Good Clinical Practice.
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Pusalkar, S., Plesescu, M., Gupta, N. et al. Biotransformation of [14C]-ixazomib in patients with advanced solid tumors: characterization of metabolite profiles in plasma, urine, and feces. Cancer Chemother Pharmacol 82, 803–814 (2018). https://doi.org/10.1007/s00280-018-3671-z
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DOI: https://doi.org/10.1007/s00280-018-3671-z