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: Neeraj Gupta, Michael J Hanley, Karthik Venkatakrishnan, Bingxia Wang, Sunil Sharma, Alberto Bessudo, Ai-Min Hui, John Nemunaitis
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 56 Issue 10 Pg. 1288-95 (10 2016) ISSN: 1552-4604 [Electronic] England
• PMID: 26872892 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Chemical References

• Boron Compounds
• Proteasome Inhibitors
• ixazomib
• Glycine

Topics

• Aged
• Aged, 80 and over
• Area Under Curve
• Biological Availability
• Boron Compounds (adverse effects, pharmacokinetics)
• Cross-Over Studies
• Diet, High-Fat
• Female
• Food-Drug Interactions
• Glycine (adverse effects, analogs & derivatives, pharmacokinetics)
• Humans
• Intestinal Absorption
• Lymphoma (metabolism)
• Male
• Meals
• Middle Aged
• Neoplasms (metabolism)
• Proteasome Inhibitors (adverse effects, pharmacokinetics)