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

• Published in: British journal of haematology Vol. 174; no. 5; pp. 748 - 759
• Main Authors: Gupta, Neeraj, Hanley, Michael J., Harvey, R. Donald, Badros, Ashraf, Lipe, Brea, Kukreti, Vishal, Berdeja, Jesus, Yang, Huyuan, Hui, Ai‐Min, Qian, Mark, Zhang, Xiaoquan, Venkatakrishnan, Karthik, Chari, Ajai
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.09.2016
• Subjects: Administration, Oral; Adult; Aged; Aged, 80 and over; Anemia - etiology; Blood Proteins - metabolism; Boron Compounds - administration & dosage; Boron Compounds - metabolism; Boron Compounds - pharmacokinetics; dialysis; Drug Dosage Calculations; Female; Glycine - administration & dosage; Glycine - analogs & derivatives; Glycine - metabolism; Glycine - pharmacokinetics; Haematological Malignancy; Humans; ixazomib; Kidney Failure, Chronic - therapy; Male; Middle Aged; multiple myeloma; Multiple Myeloma - complications; Multiple Myeloma - drug therapy; pharmacokinetics; Protease Inhibitors - administration & dosage; Protease Inhibitors - pharmacokinetics; Renal Dialysis; renal impairment; Renal Insufficiency - therapy; Research Paper; dialysis; pharmacokinetics; multiple myeloma; ixazomib; renal impairment
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/bjh.14125

Summary 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.