title: Population Pharmacokinetic Analysis of Ixazomib, an Oral Proteasome Inhibitor, Including Data from the Phase III TOURMALINE-MM1 Study to Inform Labelling.
abstract: Ixazomib is an oral proteasome inhibitor, approved in USA, Canada, Australia and Europe in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. We report a population pharmacokinetic model-based analysis for ixazomib that was pivotal in describing the clinical pharmacokinetics of ixazomib, to inform product labelling. Plasma concentration-time data were collected from 755 patients who received oral or intravenous ixazomib in once- or twice-weekly schedules in ten trials, including the global phase III TOURMALINE-MM1 study. Data were analysed using nonlinear mixed-effects modelling (NONMEM software version 7.2, ICON Development Solutions, Hanover, MD, USA). Ixazomib plasma concentrations from intravenous and oral studies were described by a three-compartment model with linear distribution and elimination kinetics, including first-order linear absorption with a lag time describing the oral dose data. Body surface area on the volume of the second peripheral compartment was the only covariate included in the final model. None of the additional covariates tested including body surface area (1.2-2.7 m2), sex, age (23-91 years), race, mild/moderate renal impairment and mild hepatic impairment were found to impact systemic clearance, suggesting that no dose adjustment is required based on these covariates. The geometric mean terminal disposition phase half-life was 9.5 days, steady-state volume of distribution was 543 L and systemic clearance was 1.86 L/h. The absolute bioavailability of an oral dose was estimated to be 58%.
authors.affiliation: Millennium Pharmaceuticals, Inc., a Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited, 40 Landsdowne Street , Cambridge, MA, 02139, USA. Neeraj.Gupta@takeda.com.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Quantitative Solutions, Breda, The Netherlands.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Diderichsen
authors.affiliation: Millennium Pharmaceuticals, Inc., a Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited, 40 Landsdowne Street , Cambridge, MA, 02139, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hanley
authors.affiliation: Millennium Pharmaceuticals, Inc., a Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited, 40 Landsdowne Street , Cambridge, MA, 02139, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Berg
authors.affiliation: Millennium Pharmaceuticals, Inc., a Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited, 40 Landsdowne Street , Cambridge, MA, 02139, USA.
authors.forename: Helgi
authors.initials: H
authors.lastname: van de Velde
authors.affiliation: Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: R Donald
authors.initials: RD
authors.lastname: Harvey
authors.affiliation: Millennium Pharmaceuticals, Inc., a Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited, 40 Landsdowne Street , Cambridge, MA, 02139, USA.
authors.forename: Karthik
authors.initials: K
authors.lastname: Venkatakrishnan
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001896:Boron Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002986:Clinical Trials as Topic; D017326:Clinical Trials, Phase III as Topic; D004348:Drug Labeling; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D061988:Proteasome Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D001896:Boron Compounds; D061988:Proteasome Inhibitors; C548400:ixazomib; D005998:Glycine