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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
Author(s) -
Gupta Neeraj,
Hanley Michael J.,
Harvey R. Donald,
Badros Ashraf,
Lipe Brea,
Kukreti Vishal,
Berdeja Jesus,
Yang Huyuan,
Hui AiMin,
Qian Mark,
Zhang Xiaoquan,
Venkatakrishnan Karthik,
Chari Ajai
Publication year - 2016
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.14125
Subject(s) - ixazomib , medicine , multiple myeloma , renal function , pharmacokinetics , urology , end stage renal disease , adverse effect , gastroenterology , pharmacology , proteasome inhibitor , hemodialysis , carfilzomib
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 ( AE s) 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 AE s was generally similar across groups, but grade 3 and 4 AE s were more frequent in the severe RI / ESRD groups versus the normal group (79%/57% vs. 45%), as were serious AE s (43%/43% vs. 15%). The PK and safety results support a reduced ixazomib dose of 3 mg in patients with severe RI / ESRD .