Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.13.97 (CYP3A4)
 6,365 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Posaconazole is a potent, extended-spectrum, investigational triazole anti-fungal that is highly active in pre-clinical in vitro and in vivo models against a wide array of yeasts and moulds, including Aspergillus, Fusarium and Zygomycetes, which are often refractory to polyenes and older azoles. In humans, orally administered posaconazole is absorbed under fed or fasted conditions; however, absorption is significantly improved when it is coadministered with food or liquid nutritional supplements and when the daily dose is divided (into two or four daily doses). Unlike newer azoles, posaconazole is not extensively metabolised by cytochrome P450 (CYP) enzymes and is primarily excreted as parent compound in the faeces. Posaconazole is a CYP3A4 inhibitor, but it does not inhibit the activity of other CYP enzymes. Therefore, in comparison with other azole anti-fungal drugs, posaconazole may have the potential for fewer drug interactions. The pharmacokinetics of posaconazole are not influenced by age, gender or race. Dose adjustments for renal or hepatic impairment do not appear to be indicated based on results from single-dose studies. Preliminary efficacy data from clinical trials are promising. As salvage therapy, posaconazole elicited complete or partial responses in 44 to 75% of patients (N = 97) with invasive fungal infections who were intolerant of, or who had disease refractory to, amphotericin B or itraconazole. In an analysis of patients with aspergillosis, a 42% success rate was observed in the posaconazole arm (n = 107) compared with a 26% success rate in the control arm (n = 86). Importantly, Kaplan-Meier analysis demonstrated a survival benefit in posaconazole-treated patients. Moreover, posaconazole yielded complete or partial responses in 71% of patients with zygomycosis (N = 24). Posaconazole appears to be well tolerated over long-term administration (>1 year) and may represent an important addition to the anti-fungal armamentarium.
 ...
PMID:Posaconazole: a potent, extended-spectrum triazole anti-fungal for the treatment of serious fungal infections. 1531 63

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 (AUC(24)/MIC)--is about 17, which is similar to the value observed for other azoles in this infection model of disseminated Candida albicans infection.
 ...
PMID:Pharmacokinetic/pharmacodynamic profile of posaconazole. 2048 49

Posaconazole (PCZ) is a relatively new addition to the azole antifungals. It has fungicidal activities against Aspergillus fumigatus, Blastomyces dermatitidis, selected Candida species, Crytopcoccus neoformans, and Trichosporon. PCZ also has fungistatic activities against Candida, Coccidioides, selected Fusarium spp., Histoplasma, Scedosporium and Zygomycetes. In addition, combining the drug with caspofungin or amphotericin B results in a synergistic interaction against A. fumigatus, C. glabrata and C. neoformans. The absorption of PCZ suspension is enhanced when given with food, nutritional supplements, and carbonated beverages. Oral administration of PCZ in divided doses also increases its bioavailability. PCZ has a large volume of distribution and is highly protein bound (>95%). The main elimination route of PCZ is fecal. PCZ is an inhibitor of the CYP3A4 enzyme; therefore, monitoring for drug-drug interactions is warranted with other CYP3A4 substrates/inhibitors/inducers. The most common adverse effects include headache, fatigue, nausea, vomiting and elevated hepatic enzymes. PCZ, with its unique antifungal activities, expands the azole class of antifungal agents. Because of its limit in formulation, PCZ oral suspension is recommended in immunocompromised patients with functional gastrointestinaltracts who fail conventional antifungal therapies or who are suspected to have a breakthrough fungal infection. However, a delayed-release tablet formulation and intravenous (IV) injection became available in 2014, expanding the use of PCZ in other patient populations, including individuals who are unable to take oral formulations.
 ...
PMID:Posaconazole: An Update of Its Clinical Use. 2897 14