A Randomized, Phase I, 3-way Crossover Study to Examine the Effects of Food on the Pharmacokinetics of Single Doses of 400 mg Posaconazole Oral Suspension in Healthy Male Taiwanese Subjects

Abstract

The pharmacokinetic parameters of a single 400-mg oral dose of posaconazole suspension, administered under fasting and fed conditions, were compared in healthy male Taiwanese volunteers. After an overnight fast, 16 subjects received a single oral dose of posaconazole suspension (400 mg) under fasting conditions or immediately after a normal-fat (700-800 calories, 30% fat) or high-fat breakfast meal (800-1000 calories, 50% fat). The treatments were administered as per the 3 × 6 Williams square design, with a 1-week washout phase between treatments. Blood samples were drawn at predetermined time points (0, 1, 2, 3, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24, 48, 72, 96, and 120 hours). All plasma concentrations of posaconazole were measured by high-performance liquid chromatography. The observed maximum plasma concentration (C max), area under the plasma concentration-time curve (AUC 0-t and AUC 0-∞), time to reach C max (t max), and plasma half-life (t 1/2) were assessed. Fourteen subjects completed the study; 2 subjects withdrew because of adverse events. Thirteen subjects were included in the pharmacokinetic analysis. Sixteen subjects were included in the safety analysis. The mean posaconazole C max, AUC 0-t, and AUC 0-∞ values were significantly lower under fasting conditions than after a normal- or a high-fat meal. The mean C max values under fasting, normal-fat, and high-fat conditions were 279.00 ± 123.32 ng/mL, 662.46 ± 251.02 ng/mL, and 608.38 ± 183.22 ng/mL, respectively (P < 0.0001); the mean AUC 0-t values under each condition were 6828.56 ± 3349.12 ng · mL(-1) · h(-1), 20,629.84 ± 8346.45 ng · mL(-1) · h(-1), and 20,741.09 ± 7681.02 ng · mL(-1) · h(-1), respectively (P < 0.0001); and the mean AUC 0-∞ values under each condition were 7304.72 ± 3444.54 ng · mL(-1) · h(-1), 21,326.65 ± 8495.01 ng · mL(-1) · h(-1), and 21,626.08 ± 8193.31 ng · mL · h(-1), respectively (P < 0.0001). The mean t max value was significantly shorter at 3.15 hours under fasting conditions than at 4.88 hours after normal- or high-fat meals (P = 0.0176). The mean t 1/2 values were 22.0, 20.8, and 22.0 hours, respectively. The posaconazole AUC increased by approximately 3-fold, C max by 2.2-fold, and t max by 1.5-fold when healthy Taiwanese subjects were administered the drug with food compared with under fasting conditions. These parameters were similar when the drug was administered with either a normal- or high-fat meal.