Influence of the Proton Pump Inhibitor Esomeprazole on the Bioavailability of Regorafenib: A Randomized Crossover Pharmacokinetic Study

Abstract

Regorafenib exposure could potentially be influenced by an interaction with acid-reducing drugs. In this crossover trial, patients were randomized into two sequence groups consisting of three phases: regorafenib intake alone, regorafenib with concomitant esomeprazole, and regorafenib with esomeprazole 3 hours prior. The primary end point was the relative difference (RD) in geometric means for regorafenib 0-24-hour area under the concentration-time curve (AUC_0-24h ) and was analyzed by a linear mixed model in 14 patients. AUC_0-24h for regorafenib alone was 55.9 μg·hour/mL (coefficient of variance (CV): 40%), and for regorafenib with concomitant esomeprazole or with esomeprazole 3 hours prior AUC_0-24h was 53.7 μg·hour/mL (CV: 34%) and 53.6 μg·hour/mL (CV: 43%), respectively. No significant differences were identified when regorafenib alone was compared with regorafenib with concomitant esomeprazole (RD: -3.9%; 95% confidence interval (CI): -20.5 to 16.1%; P = 1.0) or regorafenib with esomeprazole 3 hours prior (RD: -4.1%; 95% CI: -22.8 to 19.2%; P = 1.0). These findings indicate that regorafenib and esomeprazole can be safely combined in clinical practice.

Figure 1

Regorafenib area under the curve. Regorafenib exposure compared (a) between phase A (regorafenib alone) and phase B (regorafenib concomitantly with esomeprazole), and (b) between phases A and C (regorafenib with esomeprazole 3 hours prior). AUC _0–24, 0–24‐hour area under the concentration‐time curve; hr, hour.

Figure 2

Study procedures. QD, every day. [Colour figure can be viewed at wileyonlinelibrary.com]