Pharmacokinetics and absorption of posaconazole oral suspension under various gastric conditions in healthy volunteers

Abstract

A four-part, randomized, crossover study with healthy subjects evaluated the effects of gastric pH, the dosing frequency and prandial state, food consumption timing, and gastric motility on the absorption of posaconazole. In part 1, a single dose (SD) of posaconazole (400 mg) was administered alone or with an acidic beverage or a proton pump inhibitor (PPI), or both. In part 2, posaconazole (400 mg twice daily and 200 mg four times daily) was administered for 7 days with and without a nutritional supplement (Boost). In part 3, an SD of posaconazole (400 mg) was administered while the subjects were fasting and before, during, and after a high-fat meal. In part 4, an SD of posaconazole (400 mg) and the nutritional supplement were administered alone, with metoclopramide, and with loperamide. Compared to the results obtained with posaconazole alone, administration with an acidic beverage increased the posaconazole maximum concentration in plasma (C(max)) and the area under the concentration-time curve (AUC) by 92% and 70%, respectively, whereas a higher gastric pH decreased the posaconazole C(max) and AUC by 46% and 32%, respectively. Compared to the results obtained with posaconazole alone, posaconazole at 400 mg or at 200 mg plus the nutritional supplement increased the posaconazole C(max) and AUC by 65% and 66%, respectively, and by up to 137% and 161%, respectively. Administration before a high-fat meal increased the C(max) and the AUC by 96% and 111%, respectively, while administration during and after the meal increased the C(max) and the AUC by up to 339% and 387%, respectively. Increased gastric motility decreased the C(max) and the AUC by 21% and 19%, respectively. 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 the avoidance of proton pump inhibitors.

FIG. 1.

Mean posaconazole plasma concentration-time profiles following administration of a single oral dose of posaconazole at 400 mg alone, with an acidic carbonated beverage, with esomeprazole, or with both an acidic carbonated beverage and esomeprazole.

FIG. 2.

Mean posaconazole plasma concentration-time profiles following oral administration of posaconazole at 400 mg BID with or without a nutritional supplement (Boost) or at 200 mg QID with or without the nutritional supplement for 7 days.

FIG. 3.

Mean posaconazole plasma concentration-time profiles following administration of a single oral dose of posaconazole at 400 mg when the subject was fasted, 5 min before a high-fat meal, during a high-fat meal, or 20 min after a high-fat meal.

FIG. 4.

Mean posaconazole plasma concentration-time profiles following administration of a single oral dose of posaconazole at 400 mg with a nutritional supplement (Boost), with metoclopramide and the nutritional supplement, or with loperamide and the nutritional supplement.

FIG. 5.

Strategies for posaconazole administration to optimize absorption