In contrast, antacids, which are inorganic salts, do not raise the gastric pH above 4 or 5 5 and have a duration of action of up to 3 h when they are given with or 1 h after a meal (23)

In contrast, antacids, which are inorganic salts, do not raise the gastric pH above 4 or 5 5 and have a duration of action of up to 3 h when they are given with or 1 h after a meal (23). Studies have shown that gastric pH also affects the absorption of some other azole antifungals. (Cmax) and the area under the concentration-time curve (AUC) by 92% and 70%, respectively, whereas a higher gastric pH decreased the posaconazoleCmaxand AUC Benznidazole 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 posaconazoleCmaxand AUC by 65% and 66%, respectively, and by up to 137% and 161%, respectively. Administration before a high-fat meal increased theCmaxand the AUC by 96% and 111%, respectively, while administration during and after the meal increased theCmaxand the AUC by up to 339% and 387%, respectively. Increased gastric motility decreased theCmaxand 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. Posaconazole is Rabbit Polyclonal to p53 an extended-spectrum triazole antifungal with potent in vitro and in vivo activities against many clinically important yeasts Benznidazole and molds (16,27). The agent has demonstrated efficacy as treatment for patients with refractory invasive fungal infections (IFIs), including aspergillosis (12,26,36,39), and as antifungal prophylaxis for neutropenic patients and hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) (5,35). Posaconazole is approved for use in the United States for the prophylaxis of invasiveAspergillusandCandidainfections in immunocompromised patients and the treatment of oropharyngeal candidiasis, including infections refractory to itraconazole or fluconazole, or both (31). In the European Union, the agent is approved for use as treatment for refractory IFIs, as first-line treatment for oropharyngeal candidiasis in immunocompromised patients or patients with severe disease, and as prophylaxis for IFIs in patients receiving remission-induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes and HSCT recipients (33). The pharmacokinetics of posaconazole have been studied in healthy volunteers (6), patients with refractory IFIs or febrile neutropenia (34), patients with acute myelogenous leukemia and neutropenia (19), and HSCT recipients with GVHD (17) or neutropenia with or without mucositis (13). Posaconazole is well absorbed after oral administration and has a large volume of distribution Benznidazole (V), suggesting extensive tissue distribution (6). Posaconazole exhibits dose-proportional pharmacokinetics for doses of up to 800 mg/day (6). Posaconazole has a half-life (t1/2) of approximately 35 h, its maximum concentration in plasma (Cmax) is achieved about 3 to 5 5 h postadministration, and steady state is attained by 7 to 10 days (6,14; G. Krishna and A. Sansone-Parsons, presented at the 41st American Society of Health-System Pharmacists Midyear Clinical Meeting and Exhibition, Anaheim, CA, 3 to 7 December 2006). In healthy volunteers, age, gender, and race or ethnicity do not have a clinically relevant effect on the pharmacokinetics of posaconazole (30). Similar plasma posaconazole concentrations have been observed in adult and pediatric patients with IFIs (18). In healthy volunteers, the administration of posaconazole oral suspension with a high-fat meal, a low-fat meal, or a liquid nutritional supplement (Boost Plus) increases the mean area under the concentration-time curve (AUC) values by 4-fold, 2.6-fold, and 2.6-fold, respectively, compared with the AUCs achieved with administration in the fasted state (8,29). Under fasted conditions, administration of the total daily dose as divided doses increases the level of exposure to posaconazole compared with that achieved by use of a single dose (11). Thus, much is known about the pharmacokinetics of posaconazole. However, because of the increased use of posaconazole by seriously ill patients with gastric absorption difficulties, such as those associated with GVHD, and by patients with gastrointestinal motility disorders, including chronic diarrhea and gastrointestinal reflux disease, factors that could affect the oral absorption of posaconazole should be better defined. Therefore, the purpose of the study described here was to evaluate the pharmacokinetics of posaconazole in healthy volunteers under well-controlled conditions that simulate the various clinical scenarios that may be encountered in patients who require posaconazole therapy. Specifically, the study evaluated the effects of gastric pH, the posaconazole.