Effect of a High-Fat Meal on the Pharmacokinetics of 300-Milligram Posaconazole in a Solid Oral Tablet Formulation

Abstract

Posaconazole in oral suspension must be taken multiple times a day with food (preferably a high-fat meal) to ensure adequate exposure among patients. We evaluated the effect of food on the bioavailability of a new delayed-release tablet formulation of posaconazole at the proposed clinical dose of 300 mg once daily in a randomized, open-label, single-dose, two-period crossover study with 18 healthy volunteers. When a single 300-mg dose of posaconazole in tablet form (3 tablets ؋ 100 mg) was administered with a high-fat meal, the posaconazole area under the concentration-time curve from 0 to 72 h (AUC 0 -72 ) and maximum concentration in plasma (C max ) increased 51% and 16%, respectively, compared to those after administration in the fasted state. The median time to C max (T max ) shifted from 5 h in the fasted state to 6 h under fed conditions. No serious adverse events were reported, and no subject discontinued the study due to an adverse event. Six of the 18 subjects reported at least one clinical adverse event; all of these events were mild and short lasting. The results of this study demonstrate that a high-fat meal only modestly increases the mean posaconazole exposure (AUC), ϳ1.5-fold, after administration of posaconazole tablets, in contrast to the 4-fold increase in AUC observed previously for a posaconazole oral suspension given with a high-fat meal. P osaconazole (MK-5592) is a registered extended-spectrum triazole with demonstrated efficacy as antifungal prophylaxis for invasive fungal infections (IFIs) in high-risk patients (1, 2) and as treatment for refractory IFIs (3, 4). Posaconazole was initially developed and marketed as an oral suspension; the suspension must be administered multiple times a day and taken with food (preferably a high-fat meal) (5, 6) or a nutritional supplement or acidic beverage (6-8) to ensure adequate exposure. Reliable and adequate levels of posaconazole exposure are important to ensure continued antifungal prophylaxis. In fact, a clear exposure-efficacy relationship for posaconazole has been identified based on the results of prior pivotal studies conducted with the oral suspension (4, 9).Antifungal prophylaxis recipients routinely include the following two key populations: (i) patients with acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), or other acute hematological malignancies, who may develop neutropenia and chemotherapy-induced side effects, namely, severe nausea or vomiting; and (ii) allogeneic hematopoietic stem cell transplant (HSCT) recipients, who routinely develop graft-versus-host disease (GVHD) and its associated complications, including severe mucositis or diarrhea. Adequate food intake to obtain optimal posaconazole exposure may be difficult for these patients (10, 11). In order to overcome the burden of taking multiple doses per day together with food intake for the target population, a new solid oral tablet formulation of posaconazole has been developed that can be taken once daily and without the need for food intake to support adequate...

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