Pharmacy & Therapeutics- July 2008 - (Page 392) DRUG FORECAST leads to alterations in cellular permeability and a loss of membrane fluidity, symmetr y, and integrity.2,4 This results in either fungal cell death or inhibition of cell growth.1 Compared with other triazoles, posaconazole is more potent as an inhibitor of 14α-demethylase.4,5 The site of action for the triazole antifungals is a gene that codes for 14αdemethylase.2 Mutations at this gene have been reported with fluconazole, and cross-resistance with posaconazole may be possible.2,4 Some studies have identified a reduced susceptibility of clinical isolates of Candida albicans and Candida glabrata to posaconazole and other triazole antifungal agents.4 For this reason, data on susceptibility at each institution should be reviewed before empirical antifungal therapy is begun.4 concentration (Cmax) and area-under-thecurve (AUC) concentration were higher in subjects taking posaconazole with the drink than in participants who did not get the supplement.8 The drug’s volume of distribution is large (1,774 liters), indicative of its extensive extravascular distribution and tissue penetration.1,3 It is more than 98% protein-bound, mainly to albumin.3 Posaconazole undergoes glucuronidation in the liver, but it circulates primarily in the plasma as an unchanged compound.3 It does not undergo oxidative metabolism by the cytochrome P450 (CYP 450) enzyme system.1,3 Like other azoles, however, it inhibits the CYP 450 3A4 enzyme.1 Approximately 17% of the dose is excreted as metabolites in the urine and feces.3 Posaconazole should be used with caution in patients with severe hepatic impairment.3 The drug’s elimination half-life is 35 hours (range, 20–66 hours),3 and its total body clearance is 32 L/hour.3 Posaconazole undergoes fecal elimination; approximately 66% is excreted in the feces as the parent drug.3 The renal elimination pathway accounts for about 13% of the administered dose; therefore, no dose adjustment is indicated in patients with renal disease.3 Comparative pharmacokinetic parameters of the azoles are reviewed in Table 1. conazole, voriconazole, and amphotericin B. The minimum inhibitor y concentra tion (MIC 50) and the MIC 90 for posa conazole against Candida species were 0.063 and 1 mcg/mL, including C. glabrata, 1 and 2 mcg/mL; C. albicans, 0.031 and 0.063 mcg/mL; and Candida krusei, 0.5 and 1 mcg/mL, respectively. The MIC 50 and MIC 90 against Aspergillus species were 0.125 and 0.5 mcg/mL, respectively. The MIC50 and MIC90 against zygomycetes were 0.5 and 4 mcg/mL, respectively. In comparison, posaconazole was more active than, or within one dilution of, itraconazole, fluconazole, voriconazole, and amphotericin B against Candida and Cryptococcus species. Posaconazole was more active than or equal to the other antifungal agents against all molds such as Aspergillus species and was active against Candida and Aspergillus species that displayed resistance to fluconazole, voriconazole, and amphotericin B. Posaconazole was significantly more active than the other triazoles against zygomycetes. Torres-Narbona et al., 20079 PHARMACOKINETICS Available as an oral suspension, posaconazole is administered with food or a nutritional supplement to attain adequate plasma concentrations.3 Courtney et al., evaluating the effect of a high-fat meal on the drug’s bioavailability,6 concluded that administering posaconazole with highfat content food ensured four-fold greater systemic exposure than ingesting a posaconazole suspension or tablet with a lowfat meal.6 Ezzet et al. evaluated the bioavailability of posaconazole in a fasting state at different dosing intervals.7 The drug’s bioavailability was increased by 98% when the dose was administered ever y 12 hours and by 220% when it was given every six hours. Sansone-Parsons et al. assessed the effect of nutritional supplementation with Boost Plus (Novartis), an oral drink, on posaconazole’s pharmacokinetics. They determined that the study drug’s peak IN VITRO MICROBIOLOGICAL ACTIVITY Sabatelli et al., 20055 The in vitro activity of posaconazole was tested against approximately 19,000 clinically important strains of yeasts and molds, according to Clinical and Laboratory Standards Institute (CLSI) guidelines. The activity of posaconazole was compared with that of itraconazole, flu- An in vitro comparison of posaconazole, amphotericin B, itraconazole, voriconazole, and caspofungin against 45 clinical isolates of zygomycetes was evaluated on the basis of the CLSI standards. With its MIC 90 of 1 mcg/mL, posaconazole was more active than all of its comparators against zygomycetes. Posaconazole had the lowest MIC, compared with other antifungal agents, against Absidia species (at 1 mcg/mL) and against Mucor species (at more than 16 mcg/mL). Table 1 Comparative Pharmacokinetics of Various Triazole Antifungal Agents Pharmacokinetic Parameter Bioavailability Volume of distribution Metabolism Excretion Elimination half-life Posaconazole (Noxafil) Variable 465–1,774 liters Hepatic glucuronidation Feces, 71%–77% 35 hours Itraconazole (Sporanox) Variable 796 liters Major: cytochrome (CYP) 3A4 Feces, 3%–18% 21–64 hours 96% 350 liters Major: CYP 2C19, CYP 2C9 Minor: CYP 3A4 Urine Variable Voriconazole (Vfend) Fluconazole (Diflucan) >90% 180 liters 11% metabolized hepatically Urine, 80% Approx. 30 hours 392 P&T® • July 2008 • Vol. 33 No. 7
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