Effect of pH and Comedication on Gastrointestinal Absorption of Posaconazole

Abstract

Background and Objective: Posaconazole (Noxafil®) is an extended-spectrum triazole antifungal agent for prevention and treatment of invasive fungal infections. An inadequate dietary intake and abnormal gastric pH levels are common in critically ill patients receiving antifungal treatment with posaconazole, resulting in unpredictable bioavailability and sub-therapeutic plasma concentrations. This study was carried out to elucidate the impact of pH on posaconazole absorption and to explore the underlying mechanisms of enhanced intestinal absorption when coadministering an acidic carbonated beverage. In contrast to previously published studies, in which only plasma concentrations were determined, we also explored the gastric and intestinal behaviour of posaconazole after a single oral dose. Methods: A crossover study was performed in five healthy subjects. A single dose (10 mL) of posaconazole suspension (40 mg/mL) was administered orally in four different conditions: with 330 mL of water (condition 1); with 330 mL of a cola beverage [Coca-Cola®] (condition 2); with 330 mL of water following intake of the proton pump inhibitor esomeprazole 40 mg once daily for 3 days (condition 3); or with 330 mL of Coca-Cola® following intake of esomeprazole 40 mg once daily for 3 days (condition 4). After administration, gastrointestinal fluid and plasma samples were collected at regular time points, and posaconazole concentrations were determined. Results: Compared with administration with water, coadministration of Coca-Cola® did not alter the pH of the intraluminal environment but did significantly increase posaconazole gastric concentrations (+102%; p < 0.001) and systemic exposure (+70%; pConclusions: These results demonstrate that coadministration of Coca-Cola® has a positive effect on posaconazole bioavailability in the fasted state. However, it can only be considered a partially efficient strategy to increase absorption in patients with inadequate food intake who exhibit abnormal gastric pH levels due to coadministration of acid-suppressive agents.