Effects of Strong CYP3A Inhibition and Induction on the Pharmacokinetics of Ixazomib, an Oral Proteasome Inhibitor: Results of Drug-Drug Interaction Studies in Patients With Advanced Solid Tumors or Lymphoma and a Physiologically Based Pharmacokinetic Analysis

Abstract

At clinically relevant ixazomib concentrations, in vitro studies demonstrated that no specific cytochrome P450 (CYP) enzyme predominantly contributes to ixazomib metabolism. However, at higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms, with the estimated relative contribution being highest for CYP3A at 42%. This multiarm phase 1 study (Clinicaltrials.gov identifier: NCT01454076) investigated the effect of the strong CYP3A inhibitors ketoconazole and clarithromycin and the strong CYP3A inducer rifampin on the pharmacokinetics of ixazomib. Eighty-eight patients were enrolled across the 3 drug-drug interaction studies; the ixazomib toxicity profile was consistent with previous studies. Ketoconazole and clarithromycin had no clinically meaningful effects on the pharmacokinetics of ixazomib. The geometric least-squares mean area under the plasma concentration-time curve from 0 to 264 hours postdose ratio (90%CI) with vs without ketoconazole coadministration was 1.09 (0.91-1.31) and was 1.11 (0.86-1.43) with vs without clarithromycin coadministration. Reduced plasma exposures of ixazomib were observed following coadministration with rifampin. Ixazomib area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration was reduced by 74% (geometric least-squares mean ratio of 0.26 [90%CI 0.18-0.37]), and maximum observed plasma concentration was reduced by 54% (geometric least-squares mean ratio of 0.46 [90%CI 0.29-0.73]) in the presence of rifampin. The clinical drug-drug interaction study results were reconciled well by a physiologically based pharmacokinetic model that incorporated a minor contribution of CYP3A to overall ixazomib clearance and quantitatively considered the strength of induction of CYP3A and intestinal P-glycoprotein by rifampin. On the basis of these study results, the ixazomib prescribing information recommends that patients should avoid concomitant administration of strong CYP3A inducers with ixazomib.

Keywords: CYP3A; PBPK modeling; drug-drug interaction; ixazomib; multiple myeloma; pharmacokinetics.

© 2017, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

DDI study designs: study treatment and PK sampling during the PK cycle of the DDI study arms for (A) ketoconazole, (B) clarithromycin, and (C) rifampin. DDI indicates drug‐drug interaction; PK, pharmacokinetics.

Figure 2

Mean (± SE) plasma ixazomib concentration‐time profiles (with insets showing the first 24 hours after dosing) with and without coadministration of (A) clarithromycin or (B) rifampin.

Figure 3

Physiologically based pharmacokinetic model‐predicted and observed mean plasma concentration‐time profiles for (A) ixazomib after oral administration of 2.5 mg; (B) ixazomib 2.5 mg with and without clarithromycin coadministration; and (C) ixazomib 4 mg with and without rifampin coadministration. (A) The gray lines represent the outcomes of simulated individual trials (10 trials each containing 16 patients). The solid black line represents the mean concentration‐time data for the simulated population (N = 160 patients). The open circles represent the observed mean concentration‐time data after day 1 administration of ixazomib in the ketoconazole DDI study. (B) Simulated (black lines; 10 trials each containing 16 patients) and observed (circles; data from the clarithromycin DDI study) mean plasma concentration‐time profiles of ixazomib after a single oral dose of 2.5 mg in the presence (dashed black line, filled circles) and absence (solid black line, open circles) of multiple daily doses of clarithromycin (500 mg twice daily for 16 days). The solid/dashed black lines represent the mean concentration‐time data for the simulated population (N = 160 patients). The gray lines represent the outcomes of simulated individual trials. (C) Simulated (black lines; 10 trials each containing 16 patients) and observed (circles; data from the rifampin DDI study) mean plasma concentration‐time profiles of ixazomib after a single oral dose of 4 mg in the presence (dashed black line, filled circles) and absence (solid black line, open circles) of multiple daily doses of rifampin (600 mg daily for 14 days). The solid/dashed black lines represent the mean concentration‐time data for the simulated population (N = 160 patients). The gray lines represent the outcomes of simulated individual trials. DDI indicates drug‐drug interaction.

Figure 4

Physiologically based pharmacokinetic model‐predicted and observed geometric least‐squares mean AUC ratios for ixazomib with and without various strong CYP3A inhibitors and strong CYP3A inducers. For predicted data, error bars represent the 5th and 95th percentiles. AUC indicates area under the concentration‐time curve; CYP, cytochrome P450.