Effect of Varying Amounts of a Liquid Nutritional Supplement on the Pharmacokinetics of Posaconazole in Healthy Volunteers

The aim of this single-center, phase 1, randomized, 5 by 5 crossover, open-label study was to determine the effects of varying amounts of a nutritional supplement (Boost Plus) on the pharmacokinetics of posaconazole in 30 healthy volunteers. After an overnight fast, subjects were administered a single dose of 400 mg posaconazole oral suspension alone or following Boost Plus (8 fluid ounces [oz] [240 ml], 4 oz [120 ml], 2 oz [60 ml], or 1 oz [30 ml]). Subjects were randomized to receive all five treatments in different sequences, with a 14-day washout between treatments. Primary pharmacokinetic variables—area under the concentration-time curve from time zero to the time of the final quantifiable sample (AUC_tf), maximum observed plasma concentration (C_max), time to C_max (T_max), and relative bioavailability—were assessed up to 5 days postdose. Safety assessments included testing for adverse events, clinical laboratory tests, measurement of vital signs, physical examinations, and electrocardiograms. Posaconazole bioavailability increased almost linearly with increasing amounts of Boost Plus. Based on log-transformed data, the relative bioavailabilities (AUCs) of posaconazole were 35% (fasting), 48% (1 oz), 60% (2 oz), and 77% (4 oz) of the level reached in the presence of 8 oz Boost Plus, whereas T_max was unaffected. Compared with the levels reached under fasting conditions, posaconazole C_max and AUC values increased 3.5- and 2.9-fold, respectively, when given with 8 oz Boost Plus. Single doses of posaconazole at 400 mg alone and with 1, 2, 4, or 8 oz Boost Plus were safe and well tolerated in healthy subjects.Posaconazole, an orally available extended-spectrum triazole antifungal, has been shown to be effective for prophylaxis in immunocompromised patients who are at high risk for invasive fungal infection (IFI) (2, 12) and as a treatment for many important fungal pathogens, including Aspergillus, Candida, Cryptococcus, and Fusarium species and the zygomycetes (2, 6, 9, 12, 14).Several studies have demonstrated that the bioavailability of posaconazole is significantly enhanced when the drug is given with food (3) (posaconazole [Noxafil] oral suspension package insert; Schering-Plough, Kenilworth, NJ), presumably because of an increase in dissolution. Because patients at risk for IFI are often critically ill and may be unable to eat, do not want to eat, or are not allowed to eat due to mucositis, severe nausea, or pancreatitis (7, 10), liquid nutritional supplements are often administered, either orally or via an enteral feeding tube, to this patient population.A previous study reported that posaconazole bioavailability is significantly increased when the drug is given with 8 fluid ounces (oz) of a nutritional supplement (Boost Plus) (10). The aim of this study was to investigate the effects of varying amounts of nutritional supplement on posaconazole bioavailability, to determine whether an amount less than 8 oz would also be effective in enhancing bioavailability.(These data were presented in part at the 48th Annual ICAAC/IDSA 46th Annual Meeting, Washington, DC, 25 to 28 October 2008.)