title: The Effect of a High-Fat Meal on the Pharmacokinetics of Ixazomib, an Oral Proteasome Inhibitor, in Patients With Advanced Solid Tumors or Lymphoma.
abstract: Ixazomib is the first oral proteasome inhibitor to be investigated in the clinic. This clinical study assessed whether the pharmacokinetics of ixazomib would be altered if administered after a high-calorie, high-fat meal. In a 2-period, 2-sequence, crossover study design, adult patients with advanced solid tumors or lymphoma received a 4-mg oral dose of ixazomib as immediate-release capsules on day 1 without food (fasted, administered following an overnight fast) or with food (fed, following consumption of a high-calorie, high-fat meal), followed by another dose on day 15 in the alternate food intake condition (fasted to fed or fed to fasted). Twenty-four patients were enrolled; of these, 15 were included in the pharmacokinetic-evaluable population. Administration of ixazomib after a high-fat meal reduced both the rate and extent of absorption of ixazomib. Under fed conditions, the median time to peak plasma concentration (Tmax ) of ixazomib was delayed by approximately 3 hours compared with administration in the fasted state (1.02 hours vs 4.0 hours), and there was a 28% reduction in total systemic exposure (area under the curve, AUC) and a 69% reduction in peak plasma concentration (Cmax ). Together, the results support the administration of ixazomib on an empty stomach, at least 1 hour before or at least 2 hours after food. These recommendations are reflected in the United States Prescribing Information for ixazomib (clinicaltrials.gov identifier NCT01454076).
authors.affiliation: Millennium Pharmaceuticals, Cambridge, MA, USA. Neeraj.Gupta@takeda.com.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Millennium Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hanley
authors.affiliation: Millennium Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Karthik
authors.initials: K
authors.lastname: Venkatakrishnan
authors.affiliation: Millennium Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Bingxia
authors.initials: B
authors.lastname: Wang
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.affiliation: California Cancer Associates for Research and Excellence, San Diego, CA, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bessudo
authors.affiliation: Millennium Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Ai-Min
authors.initials: AM
authors.lastname: Hui
authors.affiliation: Mary Crowley Cancer Research Center, Dallas, TX, USA.
authors.forename: John
authors.initials: J
authors.lastname: Nemunaitis
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D001682:Biological Availability; D001896:Boron Compounds / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D059305:Diet, High-Fat; D005260:Female; D018565:Food-Drug Interactions; D005998:Glycine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D007408:Intestinal Absorption; D008223:Lymphoma / Q000378:metabolism*; D008297:Male; D062407:Meals; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D001896:Boron Compounds; D061988:Proteasome Inhibitors; C548400:ixazomib; D005998:Glycine
keywords: food effects; ixazomib; multiple myeloma; pharmacokinetics