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

Author(s): Krishna G, Moton A, Ma L, Medlock MM, McLeod J

Affiliation(s): Early Clinical Research and Experimental Medicine, Schering-Plough Research Institute, Kenilworth, New Jersey; and PPD Development LP, Austin, Texas, USA.

Publication date & source: 2008-12-15, Antimicrob Agents Chemother., [Epub ahead of print]

Publication type:

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(R) (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(R) were administered alone, with metoclopramide, and with loperamide. Compared to posaconazole alone, administration with an acidic beverage increased posaconazole Cmax and AUC by 92% and 70%, whereas higher gastric pH decreased posaconazole Cmax and AUC by 46% and 32%. Compared to posaconazole alone, posaconazole 400 mg or 200 mg plus Boost(R) increased posaconazole Cmax and AUC by 65% and 66%, and up to 137% and 161%, respectively. Administration before a high-fat meal increased Cmax and AUC by 96% and 111%, while administration during and after the meal increased Cmax and AUC by up to 339% and 387%. Increased gastric motility decreased Cmax 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.