AAC Accepts, published online ahead of print on 15 December 2008

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Antimicrob. Agents Chemother. doi:10.1128/AAC.01034-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The Pharmacokinetics and Absorption of Posaconazole Oral Suspension Under Various Gastric Conditions in Healthy Volunteers

Gopal Krishna^*, Allen Moton, Lei Ma, Matthew M. Medlock, and James McLeod

Early Clinical Research and Experimental Medicine, Schering-Plough Research Institute, Kenilworth, New Jersey; and PPD Development LP, Austin, Texas, USA

^* To whom correspondence should be addressed. Email: gopal.krishna{at}spcorp.com.

A 4-part, randomized, crossover study in healthy subjects evaluated effects of gastric pH, dose frequency and prandial state, food consumption timing, and gastric motility on posaconazole absorption. In part 1, a single dose (SD) of posaconazole 400 mg was administered alone, and with an acidic beverage, a proton pump inhibitor (PPI), and both. In part 2, posaconazole (400 mg twice daily and 200 mg four times daily) was administered for 7 days with and without Boost® (nutritional supplement). In part 3, posaconazole 400 mg SD was administered while fasting and before, during, and after a high-fat meal. In part 4, posaconazole 400 mg SD and Boost® were administered alone, with metoclopramide, and with loperamide. Compared to posaconazole alone, administration with an acidic beverage increased posaconazole C_max and AUC by 92% and 70%, whereas higher gastric pH decreased posaconazole C_max and AUC by 46% and 32%. Compared to posaconazole alone, posaconazole 400 mg or 200 mg plus Boost® increased posaconazole C_max and AUC by 65% and 66%, and up to 137% and 161%, respectively. Administration before a high-fat meal increased C_max and AUC by 96% and 111%, while administration during and after the meal increased C_max and AUC by up to 339% and 387%. Increased gastric motility decreased C_max and AUC by 21% and 19%. Strategies to maximize posaconazole exposure in patients with absorption difficulties include administration with or after a high-fat meal, with any meal or nutritional supplement, with an acidic beverage, or in divided doses; and avoidance of PPIs.

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