Drug Interactions between pazopanib and rabeprazole

GENERALLY AVOID: Coadministration with proton pump inhibitors or H2-receptor antagonists may significantly decrease the oral bioavailability of pazopanib and reduce its concentrations in plasma. The solubility of pazopanib is pH-dependent, thus an increase in pH may interfere with its absorption. According to the product labeling, pazopanib is very slightly soluble at pH 1 and practically insoluble above pH 4 in aqueous media. When pazopanib (800 mg once daily in the morning) was coadministered with esomeprazole (40 mg once daily in the evening) for 5 days in 12 patients with advanced solid tumors, mean steady-state pazopanib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by approximately 40% each. The AUCs of three metabolites were also decreased. Mean steady-state trough concentration of pazopanib was reduced to 17.3 mcg/mL, which is close to the reported threshold of >=15 mcg/mL for clinical efficacy as suggested by a phase I trial of pazopanib. However, the potential for subtherapeutic pazopanib exposure in some patients cannot be excluded.

MANAGEMENT: Concomitant use of pazopanib with proton pump inhibitors and H2-receptor antagonists should generally be avoided. If acid-suppression therapy is required, short-acting antacids should be considered, with dosing separated by several hours from pazopanib dosing. Some experts recommend administering pazopanib at least 1 hour before or 2 hours after antacids. Alternatively, a group of Dutch clinical pharmacologists and the EMA (European Medicines Agency) suggest that pazopanib may be given with a proton pump inhibitor, when necessary, if pazopanib is administered without food once daily in the evening concomitantly with the proton pump inhibitor. This recommendation is based on physiological considerations rather than actual clinical data. Since gastric pH has been reported to be lowest just before dinner in patients treated with esomeprazole daily in the evening, the thought is that impact on pazopanib solubility and absorption should be minimized when pazopanib is also administered in the evening. Similarly, when coadministration with an H2-receptor antagonist is required, it has been recommended that pazopanib be taken without food at least 2 hours before or 10 hours after a dose of the H2-receptor antagonist.

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