Rabeprazole and Capecitabine: Interaction Details

a) Coadministration of capecitabine with a proton pump inhibitor (PPI) significantly reduced capecitabine efficacy in an ad hoc analysis of the TRIO-013/LOGiC trial in patients with metastatic esophagogastric cancer randomized to capecitabine/oxaliplatin with or without lapatinib (N=545). PPI use was identified by medication records, with 20% or more overlap for the duration of study treatment, and was evenly distributed across treatment arms. Among patients treated with capecitabine/oxaliplatin (n=117), those without a concurrent PPI had a significantly prolonged median progression-free survival (PFS, 5.7 vs 4.2 months) and median overall survival (OS, 11.3 vs 9.2 months) compared with PPI-treated patients; patients treated with lapatinib did not have a difference in PFS or OS between concurrent PPI or not. Neither pharmacokinetics nor drug levels were assessed during the original trial ¹.

b) Coadministration of capecitabine monotherapy with a proton pump inhibitor (PPI) at any point was associated with an increased recurrence risk in a retrospective review of patients with early stage colorectal cancer (N=298). Patients who took a concurrent PPI while on capecitabine treatment (n=77) had a significant decrease in 5-year recurrence-free survival (RFS) rate compared with patients who did not take a PPI (n=221; 74% vs 83%), but overall survival was not effected. RFS was not different between the 2 groups when adjusting for male gender, stage III, advanced age, and poorer Eastern Cooperative Oncology Group performance status. Neither pharmacokinetics ² nor drug levels were assessed during capecitabine treatment in the patients included in this review.

c) In a randomized crossover trial, patients with solid tumors (n=22) were assigned to 2 sequence groups, each with 3 phases: esomeprazole administered 3 hours before capecitabine, capecitabine administered alone, and capecitabine administered concomitantly with cola with esomeprazole administered 3 hours before capecitabine. After esomeprazole administration, there was a nonsignificant increase of 18.9% (95% CI, -10% to 57%) in capecitabine AUC(0 to infinity) and 9.9% (95% CI, -33% to 80.1%) in Cmax compared to capecitabine alone. Capecitabine half-life was significantly longer after esomeprazole administration (0.63 vs 0.46 hours). Concomitant cola use with capecitabine did not significantly reverse the AUC effects observed after esomeprazole (relative difference, 3.3%; 95% CI, -16.3% to 27.4%). Data suggest the proposed interaction between capecitabine and esomeprazole cannot be explained by pharmacokinetics. Results from this study show capecitabine exposure is not influenced by esomeprazole coadministration and contradicts theories that proton pump inhibitors (PPIs) reduce capecitabine absorption and effect. Additional prospective studies are warranted to confirm a drug-drug interaction and to elucidate a mechanism ³.