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Effect of pH and Comedication on Gastrointestinal Absorption of Posaconazole

Monitoring of Intraluminal and Plasma Drug Concentrations

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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%; p<0.05). This enhancement could be attributed to improved posaconazole solubility in Coca-Cola® and prolonged gastric residence. Coadministration of esomeprazole led to an increased gastric pH, which was accompanied by decreased posaconazole absorption; the mean plasma and gastric area under the concentration-time curve (AUC) values decreased by 37% and 84%, respectively. Simultaneous intake of Coca-Cola® could not completely compensate for the increase in pH induced by esomeprazole; compared with the reference condition, the mean plasma and gastric AUC values were still decreased by 19% and 73%, respectively. A good correlation between plasma and gastric posaconazole concentrations was observed (r=0.8165; p<0.0001), indicating that dissolution in the stomach dictates absorption of posaconazole.

Conclusions: 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.

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Acknowledgements

Jeroen Walravens and Joachim Brouwers contributed equally to this work and should be considered joint first authors of the article.

This research was funded by grants from the Research Foundation — Flanders (FWO; Brussels, Belgium) and from the “Onderzoeksfonds” of the Katholieke Universiteit Leuven (Leuven, Belgium). Dr J. Brouwers is a postdoctoral fellow of the FWO. The authors declare that they have no conflicts of interest to disclose.

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Authors and Affiliations

  1. Laboratory for Pharmacotechnology and Biopharmacy, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N II, Herestraat 49, Box 921, 3000, Leuven, Belgium

    Jeroen Walravens, Joachim Brouwers, Pieter Annaert &  Patrick Augustijns

  2. Pharmacy Department, University Hospitals Leuven, Leuven, Belgium

    Isabel Spriet

  3. Centre for Gastroenterological Research, University Hospitals Leuven, Leuven, Belgium

    Jan Tack

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  1. Jeroen Walravens
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Correspondence to Patrick Augustijns.

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Walravens, J., Brouwers, J., Spriet, I. et al. Effect of pH and Comedication on Gastrointestinal Absorption of Posaconazole. Clin Pharmacokinet 50, 725–734 (2011). https://doi.org/10.2165/11592630-000000000-00000

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