Antimycotics for systemic use, triazole derivatives. ATC code:
Pharmacology: Pharmacodynamics: Mode of Action:
Fluconazole, a triazole antifungal agent, is a potent and specific inhibitor of fungal sterol synthesis.
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 is highly specific for fungal cytochrome P-450 dependent enzymes. Fluconazole 50 mg daily given up to 28 days has been shown not to affect testosterone plasma concentrations in males or steroid concentrations in females of child-bearing age. Fluconazole 200 mg to 400 mg daily has no clinically significant effect on endogenous steroid levels or on adrenocorticotropic hormone (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.
In animal studies, there is a correlation between minimum inhibitory concentration (MIC) values and efficacy against experimental mycoses due to Candida
spp. 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 candidemia to treatment. Similarly cure is less likely for infections caused by strains with a higher fluconazole MIC.
Microbiology: In vitro,
fluconazole displays antifungal activity against clinically common Candida
species (including C. albicans, C. parapsilosis, C. tropicalis
). C. glabrata
shows reduced susceptibility to fluconazole while C. krusei
is intrinsically resistant to fluconazole. The MICs and EUCAST epidemiological cut-off value (ECOFF) of fluconazole for C. guilliermondii
are higher than for C. albicans. The recently emerging species C. auris
tends to be relatively resistant to fluconazole.
Fluconazole also exhibits activity in vitro
against Cryptococcus neoformans
and Cryptococcus gattii
as well as the endemic moulds Blastomyces dermatitidis
, Coccidioides immitis
, Histoplasma capsulatum
and Paracoccidioides brasiliensis
Both orally and intravenously administered fluconazole was active in a variety of animal fungal infection models. Activity has been demonstrated against opportunistic mycoses, such as infections with Candida
spp., including systemic candidiasis in immunocompromised animals; with C. neoformans
, including intracranial infections; with Microsporum
spp.; and with Trichophyton
spp. Fluconazole has also been shown to be active in animal models of endemic mycoses, including infections with Blastomyces dermatitidis
; with Coccidioides immitis
, including intracranial infection; and with Histoplasma capsulatum
in normal and immunosuppressed animals.
Mechanisms of resistance:
In usually susceptible species of Candida, the most commonly encountered mechanism of resistance involves the target enzymes of the azoles, which are responsible for the biosynthesis of ergosterol. Point mutations in the gene (ERG11) encoding for the target enzyme lead to an altered target with decreased affinity for azoles. Overexpression of ERG11 results in the production of high concentrations of the target enzyme, creating the need for higher intracellular drug concentrations to inhibit all of the enzyme molecules in the cell.
The second major mechanism of drug resistance involves active efflux of fluconazole out of the cell through the activation of two types of multidrug efflux transporters; the major facilitators (encoded by MDR genes) and those of the ATP-binding cassette superfamily (encoded by CDR genes). Upregulation of the MDR gene leads to fluconazole resistance, whereas, upregulation of CDR genes may lead to resistance to multiple azoles.
Resistance in Candida glabrata
usually includes upregulation of CDR genes resulting in resistance to multiple azoles.
There have been reports of superinfection with Candida
species other than C. albicans
, which often have reduced susceptibility (C. glabrata
) or resistance to fluconazole (e.g., C. krusei
, C. auris
). Such infections may require alternative antifungal therapy.
EUCAST Reference Information (for markets referencing the EUCAST): Based on analyses of pharmacokinetic/pharmacodynamic (PK/PD) data, susceptibility in vitro
and clinical response EUCAST AFST (European Committee on Antimicrobial Susceptibility Testing - Subcommittee on Antifungal Susceptibility Testing) has determined breakpoints for fluconazole for Candida species (EUCAST Fluconazole rationale document; European Committee on Antimicrobial Susceptibility Testing, Antifungal Agents, Breakpoint tables for interpretation of MICs. 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 breakpoints for those species most frequently associated with human infection.
These breakpoints are given in the table as follows: See Table 1.
Click on icon to see table/diagram/image
CLSI Reference Information (for markets referencing the CLSI): The susceptibility breakpoints for fluconazole recognized by the Clinical and Laboratory Standards Institute (CLSI) are indicated in the table as follows. (See Table 2.)
Click on icon to see table/diagram/image
The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral route. After oral administration, fluconazole is well absorbed, and plasma levels (and systemic bioavailability) are over 90% of the levels achieved after intravenous administration. Oral absorption is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 and 1.5 hours post-dose with a plasma elimination half-life of approximately 30 hours. Plasma concentrations are proportional to dose. Ninety percent steady-state levels are reached by Days 4 to 5 with multiple once-daily dosing.
Administration of loading dose (on Day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by Day 2. The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11%-12%).
Fluconazole achieves good penetration in all body fluids studied. The levels of fluconazole in saliva and sputum are similar to plasma levels. In patients with fungal meningitis, fluconazole levels in the cerebrospinal fluid (CSF) are approximately 80% the corresponding plasma levels.
High skin concentrations of fluconazole, above serum concentrations, are achieved in the stratum corneum, epidermis-dermis and eccrine sweat. Fluconazole accumulates in the stratum corneum. At a dose of 50 mg once daily, the concentration of fluconazole after 12 days was 73 μg/g, and 7 days after cessation of treatment the concentration was still 5.8 μg/g. At the 150 mg once-a-week dose, the concentration of fluconazole in stratum corneum on Day 7 was 23.4 μg/g, and 7 days after the second dose was still 7.1 μg/g.
Concentration of fluconazole in nails after 4 months of 150 mg once-a-week dosing was 4.05 μg/g in healthy and 1.8 μg/g in diseased nails; and, fluconazole was still measurable in nail samples 6 months after the end of therapy.
The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged drug. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites.
The long plasma elimination half-life provides the basis for single-dose therapy for vaginal candidiasis, once-daily and once-weekly dosing for other indications.
A study compared the saliva and plasma concentrations of a single fluconazole 100 mg dose administered in a capsule or in an oral suspension* by rinsing and retaining in mouth for 2 minutes and swallowing. The maximum concentration of fluconazole in saliva after the suspension was observed 5 minutes after ingestion, and was 182 times higher than the maximum saliva concentration after the capsule which occurred 4 hours after ingestion. After about 4 hours, the saliva concentrations of fluconazole were similar. The mean AUC(0-96)
in saliva was significantly greater after the suspension compared to the capsule. There was no significant difference in the elimination rate from saliva or the plasma pharmacokinetic parameters for the two formulations.
*Fluconazole oral suspension is not available locally.
A pharmacokinetic study in 10 lactating women, who had temporarily or permanently stopped breast-feeding their infants, evaluated fluconazole concentrations in plasma and breast milk for 48 hours following a single 150 mg dose of fluconazole (Diflucan). Fluconazole was detected in breast milk at an average concentration of approximately 98% of those in maternal plasma. The mean peak breast milk concentration was 2.61 mg/L at 5.2 hours post-dose.
Pharmacokinetics in Children:
In children, pharmacokinetic data have been reported as follows in Table 3: See Table 3.
Click on icon to see table/diagram/image
In premature newborns (gestational age around 28 weeks), intravenous administration of fluconazole of 6 mg/kg was given every third day for a maximum of five doses while the premature newborns remained in the intensive care unit. The mean half-life (hours) was 74 (range 44-185) on Day 1, which decreased with time to a mean of 53 (range 30-131) on Days 7 and 47 (range 27-68) on Day 13.
The AUC (μg.h/mL) was 271 (range 173-385) on Day 1, which increased with a mean of 490 (range 292-734) on Day 7 and decreased with a mean of 360 (range 167-566) on Day 13.
The volume of distribution (mL/kg) was 1183 (range 1070-1470) on Day 1, which increased with time to a mean of 1184 (range 510-2130) on Day 7 and 1328 (range 1040-1680) on Day 13.
Pharmacokinetics in Elderly:
A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax
was 1.54 μg h/mL and occurred at 1.3 hours post dose. The mean AUC was 76.4 ± 20.3 μg.h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministration of diuretics did not significantly alter the AUC or Cmax
. In addition, creatinine clearance (74 mL/min), the percent of drug recovered unchanged in urine (0-24 hours, 22%) and the fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristic of this group. A plot of each subject's terminal elimination half-life versus creatinine clearance compared to the predicted half-life-creatinine clearance curve derived from normal subjects and subjects with varying degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence limit of the predicted half-life-creatinine clearance curves. These results are consistent with the hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects compared to normal young male volunteers are due to the decreased kidney function that is expected in the elderly.
Toxicology: Preclinical Safety Data:
Carcinogenesis: Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5 or 10 mg/kg/day (approximately 2-7 times the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas.
Mutagenesis: Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in four strains of Salmonella typhimurium
, and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo
(murine bone marrow cells, following oral administration of fluconazole) and in vitro
(human lymphocytes exposed to fluconazole at 1000 μg/mL) showed no evidence of chromosomal mutations.
Impairment of Fertility: Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5 mg/kg, 10 mg/kg or 20 mg/kg or with parenteral doses of 5 mg/kg, 25 mg/kg or 75 mg/kg, although the onset of parturition was slightly delayed at 20 mg/kg orally. In an intravenous perinatal study in rats at 5 mg/kg, 20 mg/kg and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg (approximately 5-15 times the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The disturbances in parturition were reflected by a slight increase in the number of still-born pups and decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent with the species specific estrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole (see Pharmacodynamics as previously mentioned).