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).

Keywords: food effects; ixazomib; multiple myeloma; pharmacokinetics.

© 2016 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Ixazomib food‐effect study design. Arrows indicate dosing or sampling days. In cycle 2 and subsequent cycles (all 28‐day cycles), all patients received only ixazomib, 4 mg daily, on days 1, 8, and 15. Ixazomib was administered for a maximum of 12 cycles unless disease progression or unacceptable toxicity occurred. The starting dose for cycle 2 was 4 mg, with the option of dose escalation to 5.3 mg at cycle 4 and beyond. PK, pharmacokinetics.

Figure 2

Mean plasma concentration‐time profiles of ixazomib under fasted and fed conditions (n = 15). The inset shows the mean plasma ixazomib concentrations over the first 24 hours after dosing. Error bars in the inset figure indicate standard deviation.