Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02AC01.

Mechanism of action

Fluconazole is a triazole antifungal agent. Its primary mode of action is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of fluconazole. Fluconazole has been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems.

Fluconazole 50 mg daily given up to 28 days has been shown not to effect testosterone plasma concentrations in males or steroid concentration in females of child-bearing age. Fluconazole 200 mg to 400 mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers. Interaction studies with antipyrine indicate that single or multiple doses of fluconazole 50 mg do not affect its metabolism.

Susceptibility in vitro:
In vitro, fluconazole displays antifungal activity against most clinically common Candida species Date: 31/03/21
Baxter Pharmaceuticals India Private Limited 


(including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows a wide range of susceptibility while C. krusei is resistant to fluconazole.
Fluconazole also exhibits activity in vitro against Cryptococcus neoformans and Cryptococcus gattii as well as the endemic moulds Blastomyces dermatiditis, Coccidioides immitis, Histoplasma capsulatum and Paracoccidioides brasiliensis.

Pharmacokinetic/pharmacodynamic relationship Pantone



In animal studies, there is a correlation between MIC values and efficacy against experimental mycoses due to Candidaspp. In clinical studies, there is an almost 1:1 linear relationship between the AUC and the dose of fluconazole. There is also a direct though imperfect relationship between the AUC or dose and a successful clinical response of oral candidosis and to a lesser extent candidaemia to treatment. Similarly cure is less likely for infections caused by strains with a higher fluconazole MIC.

Mechanisms of resistance
Candida spp have developed a number of resistance mechanisms to azole antifungal agents.
Fungal strains which have developed one or more of these resistance mechanisms are known to exhibit high minimum inhibitory concentrations (MICs) to fluconazole which impacts adversely (5)


 efficacy in vivo and clinically.
There have been reports of superinfection with Candida species other than C. albicans, which are Pantone


 often inherently not susceptible to fluconazole (e.g. Candida krusei). Such cases may require alternative antifungal therapy.

Breakpoints (according to EUCAST)
Based on analyses of pharmacokinetic/pharmacodynamic (PK/PD) data, susceptibility in vitro and clinical response EUCAST-AFST (European Committee on Antimicrobial susceptibility Testing- Size of Artwork (In mm) : 600x175


 subcommittee on Antifungal Susceptibility Testing) has determined breakpoints for fluconazole for Candida species (EUCAST Fluconazole rational document (2007)-version 2). These have been divided into non-species related breakpoints; which have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species, and species related GSM of Paper/Board : 60 GSM


 breakpoints for those species most frequently associated with human infection. These breakpoints are given in the table below:
Pantone



Antifungal     Species-related breakpoints (S≤/R>)                                    Non-species Plant Location : Injectable


 related
Artwork Control Key No.:



A breakpoints
Artwork Req. No: 27737


S≤/R>
Candida           Candida      Candida      Candida        Candida (4)


 albicans          glabrata     krusei       parapsilosis   tropicalis Fluconazole 2/4               IE           --           2/4            2/4            2/4 Language : English



S = Susceptible, R = Resistant
A. = Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for organisms that do not have specific breakpoints.
-- = Susceptibility testing not recommended as the species is a poor target for therapy with the Pantone


 medicinal product.
IE = There is insufficient evidence that the species in question is a good target for therapy with the medicinal product.

Pharmacokinetic Properties