A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end-stage renal disease requiring haemodialysis

• Type of Material: Article
• Authors: Neeraj Gupta, Millennium Pharmaceuticals Inc.; Michael J. Hanley, Millennium Pharmaceuticals Inc.; R. Harvey, Emory University; Ashraf Badros, University of Maryland; Brea Lipe, University of Kansas; Vishal Kukreti, University Health Network; Jesus Berdeja, Sarah Cannon Cancer Center; Huyuan Yang, Millennium Pharmaceuticals Inc.; Ai-Min Hui, Millennium Pharmaceuticals Inc.; Mark Qian, Millennium Pharmaceuticals Inc.; Xiaoquan Zhang, Millennium Pharmaceuticals Inc.; Karthik Venkatakrishnan, Millennium Pharmaceuticals Inc.; Ajai Chari, Mount Sinai Medical Center
• Language: English
• Date: 2016-09-01
• Publisher: Wiley
• Publication Version: Final Published Version
• Copyright Statement: © 2016 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1111/bjh.14125
• Title of Journal or Parent Work: British Journal of Haematology
• ISSN: 0007-1048
• Volume: 174
• Issue: 5
• Start Page: 748
• End Page: 759
• Grant/Funding Information: This work was funded by Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
• Keywords: Science & Technology; COMBINATION; REVERSIBILITY; BORTEZOMIB; Life Sciences & Biomedicine; multiple myeloma; renal impairment; Hematology; CARFILZOMIB; dialysis; ixazomib; INVESTIGATIONAL PROTEASOME INHIBITOR; pharmacokinetics; LENALIDOMIDE; DEXAMETHASONE; FAILURE; OPEN-LABEL; IMPACT
• Research Categories: Health Sciences, Oncology; Health Sciences, Pharmacology

Abstract

Renal impairment (RI) is a major complication of multiple myeloma (MM). This study aimed to characterize the single-dose pharmacokinetics (PK) of the oral proteasome inhibitor, ixazomib, in cancer patients with normal renal function [creatinine clearance (CrCl) ≥90 ml/min; n = 20), severe RI (CrCl <30 ml/min; n = 14), or end-stage renal disease requiring haemodialysis (ESRD; n = 7). PK and adverse events (AEs) were assessed after a single 3 mg dose of ixazomib. Ixazomib was highly bound to plasma proteins (~99%) in all renal function groups. Unbound and total systemic exposures of ixazomib were 38% and 39% higher, respectively, in severe RI/ESRD patients versus patients with normal renal function. Total ixazomib concentrations were similar in pre- and post-dialyser samples collected from ESRD patients; therefore, ixazomib can be administered without regard to haemodialysis timing. Except for anaemia, the incidence of the most common AEs was generally similar across groups, but grade 3 and 4 AEs were more frequent in the severe RI/ESRD groups versus the normal group (79%/57% vs. 45%), as were serious AEs (43%/43% vs. 15%). The PK and safety results support a reduced ixazomib dose of 3 mg in patients with severe RI/ESRD.