title: 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.
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.
authors.affiliation: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hanley
authors.affiliation: Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: R Donald
authors.initials: RD
authors.lastname: Harvey
authors.affiliation: University of Maryland, Baltimore, MD, USA.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Badros
authors.affiliation: University of Kansas Clinical Research Center, Fairway, KS, USA.
authors.forename: Brea
authors.initials: B
authors.lastname: Lipe
authors.affiliation: University Health Network, Toronto, ON, Canada.
authors.forename: Vishal
authors.initials: V
authors.lastname: Kukreti
authors.affiliation: Sarah Cannon Cancer Center, Nashville, TN, USA.
authors.forename: Jesus
authors.initials: J
authors.lastname: Berdeja
authors.affiliation: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
authors.forename: Huyuan
authors.initials: H
authors.lastname: Yang
authors.affiliation: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
authors.forename: Ai-Min
authors.initials: AM
authors.lastname: Hui
authors.affiliation: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Qian
authors.affiliation: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
authors.forename: Xiaoquan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
authors.forename: Karthik
authors.initials: K
authors.lastname: Venkatakrishnan
authors.affiliation: Mount Sinai Medical Center, New York, NY, USA.
authors.forename: Ajai
authors.initials: A
authors.lastname: Chari
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000209:etiology; D001798:Blood Proteins / Q000378:metabolism; D001896:Boron Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D054796:Drug Dosage Calculations; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D007676:Kidney Failure, Chronic / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000150:complications / Q000188:drug therapy*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006435:Renal Dialysis; D051437:Renal Insufficiency / Q000628:therapy*
chemical_list: D001798:Blood Proteins; D001896:Boron Compounds; D011480:Protease Inhibitors; C548400:ixazomib; D005998:Glycine
keywords: dialysis; ixazomib; multiple myeloma; pharmacokinetics; renal impairment