The pharmacokinetics, safety, and tolerability of posaconazole, an investigational triazole antifungal, were evaluated following the administration of rising single and multiple oral doses. A total of 103 healthy adults were enrolled in two phase I trials. Each study had a double-blind, placebo-controlled, parallel-group design with a rising single-dose (RSD) or rising multiple-dose (RMD) scheme. In the RSD study, subjects received single doses of posaconazole oral tablets (50 to 1,200 mg) or placebo. In the RMD study, subjects received posaconazole oral tablets (50 to 400 mg) or placebo twice daily for 14 days. By using model-independent methods, the area under the plasma concentration-time curve and the maximum concentration in plasma were determined and used to assess dose proportionality. In the RSD study, the levels of posaconazole in plasma increased proportionally between the 50-and 800-mg dose range, with saturation of absorption occurring above 800 mg. Dose proportionality was also observed in the RMD study. In both studies, the apparent volume of distribution was large (range, 343 to 1,341 liters) and the terminal-phase half-life was long (range, 25 to 31 h). Posaconazole was well tolerated at all dose levels, and the adverse events were not dose dependent. No clinically significant changes in clinical laboratory test values or electrocardiograms were observed. Following the administration of single and twice-daily rising doses, the level of posaconazole exposure increased in a dose-proportional manner. The long elimination-phase half-life of posaconazole supports once-or twice-daily dosing in clinical trials; however, additional studies are required to determine if further division of the dose will enhance exposure.The evolution of oral triazole antifungal agents began in the 1980s with the introduction of fluconazole and itraconazole for the treatment of systemic fungal infections. In recent years, the patterns of Candida infections have changed. Previously, Candida albicans was the most prevalent cause of Candida infections, whereas in recent times, other Candida species, such as C. glabrata and C. krusei, have become common infectioncausing pathogens (6). In addition to this shift in species, fluconazole-and itraconazole-resistant Candida strains have emerged, prompting clinicians to search for alternative treatment options. The emergence of new fungal diseases caused by fungi that were previously not thought to be pathogenic has also limited the usefulness of older triazole compounds for the treatment of invasive infections, especially in immunocompromised patients. For example, fusariosis and zygomycosis are increasingly common; however, the treatments for these infections are limited (23). In light of the need for more potent and broad-spectrum therapeutic options, posaconazole (SCH 56592), a novel oral triazole derivative structurally similar to itraconazole (Fig. 1), is in development for the treatment of invasive fungal infections.Posaconazole has enhanced activity against many old, new, and ...

AimsThis randomized, crossover, single-dose study evaluated the relative oral bioavailability of posaconazole suspension and coprecipitate tablet formulations. Additionally, the study determined whether systemic exposure to posaconazole was affected by prandial status or by the fat content of a meal. MethodsThis was a randomized, open-label, four-way crossover, single-dose study in 20 healthy men. Posaconazole pharmacokinetics were evaluated over 72 h following a single oral dose of posaconazole suspension (200 mg/5 ml) administered with a high-fat meal, a nonfat breakfast, or after a 10 h fast, or posaconazole tablets (2 ¥ 100 mg) administered with a high-fat meal. ResultsThe posaconazole suspension showed a significant increase in bioavailability compared with the tablet (increase in AUC(0,72 h) = 137% (90% confidence interval (CI) 119%, 156% and C max = 123% (90% CI 104%, 146%). The mean increases in AUC(0,72 h) and C max values were about 400% when administered with a high-fat meal compared with administration of the suspension in the fasting state (AUC(0,72 h) 90% CI 343%, 448%; C max 90% CI 352%, 493%). Administration of the suspension with a nonfat meal enhanced exposure, resulting in an increase in AUC(0,72 h) of 264% (90% CI 231%, 302%) and in C max of 296% (90% CI 250%, 350%) relative to the fasted state. ConclusionsThe suspension formulation of posaconazole was associated with enhanced systemic exposure and increased relative bioavailability compared with the tablet. Food substantially enhanced the rate and extent of posaconazole absorption in healthy subjects.

No abstract

Posaconazole is a potent broad-spectrum azole antifungal agent in clinical development for the treatment of invasive fungal infections. This study evaluated the potential for a pH-dependent pharmacokinetic interaction between posaconazole and an antacid (Mylanta), under fasting and nonfasting conditions. Twelve men completed this randomized, four-period crossover, single-dose study. Subjects received 200 mg of posaconazole following a 10-h fast, with 20 ml of Mylanta and a 10-h fast, with 20 ml of Mylanta and a high-fat breakfast, and with a high-fat breakfast alone. Antacid coadministration had no statistically significant effects on posaconazole bioavailability under fasting or nonfasting conditions. In the fasting state, antacid slightly increased the relative oral bioavailability of posaconazole by 15% (P ‫؍‬ 0.296); in the nonfasting state, antacid decreased the relative bioavailability of posaconazole by 12% (P ‫؍‬ 0.352). Food increased the relative oral bioavailability of posaconazole by 400% (P ‫؍‬ 0.001). In conclusion, the effect of antacid on posaconazole exposure in the fasting or nonfasting state was small and is not considered clinically significant.

The bioavailability of drugs that do not undergo significant intestinal or hepatic metabolism, such as fexofenadine, may be altered when administered with agents that influence drug transport mechanisms.

These data suggest that divided daily dose administration (every 12 or 6 hours) significantly increases posaconazole exposure under fasted conditions.

No abstract

The impact of renal insufficiency on the dispositions of 300 mg of orally administered ceftibuten-cis, a new broad-spectrum oral cephalosporin, and its primary metabolite ceftibuten-trans was characterized in 30 adult subjects. Subjects were divided into five groups of six subjects each on the basis of their 24-h ambulatory creatinine clearances (CLCR). The apparent total body clearance (CLP/F; where F is absolute bioavailability) and renal clearance of ceftibuten-cis were significantly lower in subjects with end-stage renal disease (on maintenance hemodialysis; group V) and in those with severe (CLCR, 5 to 29 ml/min; group IV) and moderate (CLCR, 30 to 49 ml/min; group III) renal insufficiency than in those with mild renal insufficiency (CLCR, 50 to 80 ml/min; group II) or normal renal function (CLCR, greater than 80 ml/min; group I). A significant correlation was observed between CLCR and ceftibuten-cis CLP/F. The mean apparent steady-state volume of distribution (V beta/F) of ceftibuten-cis ranged from 0.21 to 0.24 liter/kg in subjects in group I, II, III, and IV. V beta/F was significantly greater in the group V subjects with end-stage renal disease (V beta/F, 0.39 +/- 0.27 liters/kg). These changes in V beta/F cannot be separated from possible changes in bioavailability. The maximum concentration of ceftibuten-trans in plasma was significantly higher and occurred significantly later in group IV subjects than it did in subjects in the other groups.(ABSTRACT TRUNCATED AT 250 WORDS)