Re-thinking the possible interaction between proton pump inhibitors and capecitabine

Proton Pump Inhibitors (PPI) rank within the top ten most prescribed medications in Europe and USA. A high frequency of PPI use has been reported amongst patients undergoing chemotherapy, to mitigate treatment-induced gastritis or gastro-oesophageal reflux. Several recent, mostly retrospective, observational studies have reported inferior survival outcomes among patients on capecitabine who concomitantly use PPI. Whilst this association is yet to be definitively established, given the prominence of capecitabine as an anti-cancer treatment with multiple indications, these reports have raised concern within the oncological community and drug regulatory bodies worldwide. Currently, the leading mechanism of interaction postulated in these reports has focussed on the pH altering effects of PPI and how this could diminish capecitabine absorption, leading to a decrease in its bioavailability. In this discourse, we endeavour to summarise plausible pharmacokinetic interactions between PPI and capecitabine. We provide a basis for our argument against the currently proposed mechanism of interaction. We also highlight the long-term effects of PPI on health outcomes, and how PPI use itself could lead to poorer outcomes, independent of capecitabine.