A phase I study to assess the mass balance, excretion, and pharmacokinetics of [14C]-ixazomib, an oral proteasome inhibitor, in patients with advanced solid tumors

Neeraj Gupta, Steven Zhang, Sandeepraj Pusalkar, Mihaela Plesescu, Swapan Chowdhury, Michael J Hanley, Bingxia Wang, Cindy Xia, Xiaoquan Zhang, Karthik Venkatakrishnan, Dale R Shepard, Neeraj Gupta, Steven Zhang, Sandeepraj Pusalkar, Mihaela Plesescu, Swapan Chowdhury, Michael J Hanley, Bingxia Wang, Cindy Xia, Xiaoquan Zhang, Karthik Venkatakrishnan, Dale R Shepard

Abstract

This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics (PK), and safety of ixazomib in patients with advanced solid tumors. In Part A of the study, patients received a single 4.1 mg oral solution dose of [14C]-ixazomib containing ~500 nCi total radioactivity (TRA), followed by non-radiolabeled ixazomib (4 mg capsule) on days 14 and 21 of the 35-day PK cycle. Patients were confined to the clinic for the first 168 h post dose and returned for 24 h overnight clinic visits on days 14, 21, 28, and 35. Blood, urine, and fecal samples were collected during Part A to assess the mass balance (by accelerator mass spectrometry), excretion, and PK of ixazomib. During Part B of the study, patients received non-radiolabeled ixazomib (4 mg capsules) on days 1, 8, and 15 of 28-day cycles. After oral administration, ixazomib was rapidly absorbed with a median plasma Tmax of 0.5 h and represented 70% of total drug-related material in plasma. The mean total recovery of administered TRA was 83.9%; 62.1% in urine and 21.8% in feces. Only 3.23% of the administered dose was recovered in urine as unchanged drug up to 168 h post dose, suggesting that most of the TRA in urine was attributable to metabolites. All patients experienced a treatment-emergent adverse event, which most commonly involved the gastrointestinal system. These findings suggest that ixazomib is extensively metabolized, with urine representing the predominant route of excretion of drug-related material.Trial ID: ClinicalTrials.gov # NCT01953783.

Keywords: ADME; AMS; Ixazomib; Mass balance; Pharmacokinetics; Total radioactivity.

Conflict of interest statement

Conflicts of interest

NG, SZ, SP, MP, SC, MJH, BW, CX, XZ, and KV are employees of Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. DRS has no conflicts of interest to report.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Figures

Fig. 1
Fig. 1
Treatment schema
Fig. 2
Fig. 2
Mean plasma concentration–time profiles for ixazomib and TRA, and whole blood TRA–time profile following administration of a single 4.1 mg oral solution dose of [14C]-ixazomib. TRA total radioactivity
Fig. 3
Fig. 3
(a) Mean percentage cumulative recovery in urine over time for unchanged ixazomib and ixazomib-related TRA, and (b) mean percentage cumulative urine, fecal, and total recovery over time for ixazomib-related TRA, following administration of a single oral solution dose of 4.1 mg [14C]-ixazomib. TRA total radioactivity

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