In the United States and European Union, the oral proteasome inhibitor ixazomib ((R)-(1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)boronic acid) is approved, in combination with lenalidomide-dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. In total, ixazomib is now approved in 40 countries worldwide. In vitro studies indicate that ixazomib is metabolized by multiple cytochrome P450 (CYP) enzymes and non-CYP proteins; at close to clinical concentrations following oral administration of 4.0 mg ixazomib, non-CYP mediated clearance was observed and appeared to play a major role in ixazomib clearance in vitro. A phase I study of [14C]-ixazomib was conducted to assess mass balance, pharmacokinetics, and metabolism following administration of a single 4.1 mg oral dose of [14C]-ixazomib (~500 nCi), using accelerator mass spectrometry. Results showed that ixazomib was rapidly absorbed (median Tmax 0.5 hours) and extensively metabolized, with very little unchanged ixazomib excreted in the urine (3% of dose administered), and urinary excretion representing the predominant route of excretion of drug-related material.1 As part of this study, we also performed metabolite profiling of ixazomib in plasma and excreta in four patients. On average, 53.6% and 22.6% of the administered dose was recovered in urine and feces, respectively, for a total recovery of 76.2% in excreta by 35 days post-dose (N=4). In addition to ixazomib (54.2% of plasma total radioactivity [TRA]), M3 (7.91% of plasma TRA), M12 (18.9% of plasma TRA), and M21 (10.6% of plasma TRA) were the major circulating metabolites identified in plasma. Loss of the boronic acid moiety is expected to result in the loss of pharmacological activity, and as none of these major metabolites contain a boronic acid moiety, they are unlikely to be pharmacologically active. Based upon the plasma, urine, and fecal metabolite profiles, hydrolysis of ixazomib to M12, deboronation to M1, and deamination to M3 are the major clearance pathways of ixazomib in humans. Hydrolysis of ixazomib to M12 was the most significant metabolism pathway, contributing to 31.1% of the 76.2% of the total dose excreted in urine and feces over 35 days postdose. The metabolite profile of 0- to 816-hour plasma is similar to that of 0- to 24-hour plasma, indicating that the metabolite profile is relatively unchanged through 816 hours (>3 t1/2z). Additionally, the similarity of urine and fecal profiles in pooled samples over 0 to 168 hours, on Day 21, and on Day 35 indicates that the clearance mechanisms of ixazomib are time-independent. Taken together, these findings are consistent with hydrolytic and oxidative deboronation as the primary biotransformation pathways of ixazomib and formation rate‑limited clearance of metabolites.
1. Gupta N, et al. A phase 1 mass balance study of ixazomib, an oral proteasome inhibitor, using accelerator mass spectrometry in patients with advanced solid tumors. Clinical Pharmacology & Therapeutics. 101(Suppl 1): p.S30, 2017