Pharmacokinetic/Pharmacodynamic Profile of Posaconazole

Posaconazole is a recently approved lipophilic triazole antifungal agent that exhibits potent and broad-spectrum antifungal activity in vitro and in vivo against most Candida spp., Cryptococcus neoformans, Aspergillus spp., many Zygomycetes, endemic fungi and dermatophytes. It has been documented that posaconazole has potency and spectrum of activity similar to those of itraconazole and superior to those of fluconazole against clinically important isolates of Candida spp., C. neoformans and Aspergillus spp. This new triazole has been developed for the treatment of fungal infections, which most often occur in severely immunocompromised patients, such as organ transplant patients or cancer patients undergoing chemotherapy. Since posanconazole has low solubility in aqueous and acidic media, its absorption is dose limited and significantly dependent upon food intake. The time to reach the maximum plasma concentration has been reported to be 5–8 hours following oral administration of a single dose. The relative bioavailability of posaconazole has been estimated to be significantly different among regimens and has been observed to be significantly increased by administration in divided doses. Posaconazole binds predominantly to albumin, and the extent of protein binding is high (>98%). Posaconazole has a large mean apparent volume of distribution after oral administration (V_d/F), which is approximately 5–25 L/kg, suggesting extensive extravascular distribution and penetration into intracellular spaces. The V_d/F is influenced by the dosage regimen. Since food significantly increases its bioavailability, posaconazole should be administered with a full meal whenever possible, to ensure optimal absorption. Posaconazole primarily circulates in plasma and then is widely distributed to the tissues and is slowly eliminated. Posaconazole is not metabolized to a significant extent through the cytochrome P450 (CYP) enzyme system and also has no effect on the CYP isoenzymes of 1A2, 2C8, 2C9, 2D6 and 2E1. The limited metabolism of posaconazole is mediated predominantly through phase 2 biotransformations via uridine diphosphate glucuronosyltransferase enzyme pathways. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Since posaconazole is an inhibitor primarily of CYP3A4, plasma concentrations of drugs that are predominantly metabolized by CYP3A4 may be increased by posaconazole. Posaconazole has a median terminal elimination half-life of 15–35 hours. The renal elimination of posaconazole is less than 1 mL/h, which is negligible compared with the mean total oral clearance of 16.3 L/h.

Posaconazole shows potent in vitro activity against yeasts such as Candida spp. and C. neoformans, and against a range of moulds such as Aspergillus spp., as well as many dimorphic fungi and dermatophytes. Posaconazole has been shown to improve survival and/or to reduce the fungal tissue burden in animals infected with Blastomyces dermatitidis, C. neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Coccidioides immitis or Pseudallescheria boydii. The predictive pharmacokinetic/pharmacodynamic parameter for posaconazole treatment efficacy — the ratio between the mean free-drug area under the plasma concentration-time curve from 0 to 24 hours and the minimum inhibitory concentration (AUC₂₄/MIC) — is about 17, which is similar to the value observed for other azoles in this infection model of disseminated Candida albicans infection.