Fluconazole pharmacokinetics and molecular data

Pharmacokinetics and molecular data
Mechanism Pharmacokinetics/metabolism (adults) Pharmacokinetics (children) Pharmacokinetics (elderly) Microbiology
 * Peak plasma concentrations
 * Steady-state concentrations

Mechanism
Fluconazole is a highly selective inhibitor of fungal cytochrome P-450 sterol C-14 alpha-demethylation. Mammalian cell demethylation is much less sensitive to Fluconazole inhibition. The subsequent loss of normal sterols correlates with the accumulation of 14 alpha-methyl sterols in fungi and may be responsible for the fungistatic activity of Fluconazole. Return to top

Pharmacokinetics/metabolism (adults)
The pharmacokinetic properties of Fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, the bioavailability of orally administered Fluconazole is over 90% compared with intravenous administration. Bioequivalence was established between the 100 mg tablet and both suspension strengths when administered as a single 200 mg dose. In normal volunteers, Fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites. The pharmacokinetics of Fluconazole are markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of Fluconazole may need to be reduced in patients with impaired renal function. A 3-hour hemodialysis session decreases plasma concentrations by approximately 50%. In normal volunteers, Fluconazole administration (doses ranging from 200 mg to 400 mg once daily for up to 14 days) was associated with small and inconsistent effects on testosterone concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol response. Return to top

Peak plasma concentrations
Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of approximately 30 hours (range: 20–50 hours) after oral administration. In fasted normal volunteers, administration of a single oral 400 mg dose of Fluconazole leads to a mean Cmax of 6.72 µg/mL (range: 4.12 to 8.08 µg/mL) and after single oral doses of 50–400 mg, Fluconazole plasma concentrations and AUC (area under the plasma concentration time curve) are dose proportional. Administration of a single oral 150 mg tablet of Fluconazole to ten lactating women resulted in a mean Cmax of 2.61 µg/mL (range: 1.57 to 3.65 µg/mL). Return to top

Steady-state concentrations
Steady-state concentrations are reached within 5–10 days following oral doses of 50–400 mg given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose results in plasma concentrations close to steady-state by the second day. The apparent volume of distribution of Fluconazole approximates that of total body water. Plasma protein binding is low (11–12%). Following either single- or multiple-oral doses for up to 14 days, Fluconazole penetrates into all body fluids studied. In normal volunteers, saliva concentrations of Fluconazole were equal to or slightly greater than plasma concentrations regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum concentrations of Fluconazole following a single 150 mg oral dose were equal to plasma concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, Fluconazole concentrations in the CSF are approximately 80% of the corresponding plasma concentrations. A single oral 150 mg dose of Fluconazole administered to 27 patients penetrated into vaginal tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours following dosing. A single oral 150 mg dose of Fluconazole administered to 14 patients penetrated into vaginal fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following dosing. Return to top

Pharmacokinetics (children)
In children, the following pharmacokinetic data {Mean(%cv)} have been reported: Clearance corrected for body weight was not affected by age in these studies. Mean body clearance in adults is reported to be 0.23 (17%) mL/min/kg. In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within 36 hours of birth was 0.180 (35%, N=7) mL/min/kg, which increased with time to a mean of 0.218 (31%, N=9) mL/min/kg six days later and 0.333 (56%, N=4) mL/min/kg 12 days later. Similarly, the half life was 73.6 hours, which decreased with time to a mean of 53.2 hours six days later and 46.6 hours 12 days later. Return to top

Pharmacokinetics (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 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was 76.4±20.3 mcg∙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 AUC or Cmax. In addition, creatinine clearance (74 mL/min), the percent of drug recovered unchanged in urine (0–24 hr, 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 with 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 with normal young male volunteers are due to the decreased kidney function that is expected in the elderly. Return to top

Microbiology
Fluconazole exhibits in vitro activity against Cryptococcus neoformans and Candida spp. Fungistatic activity has also been demonstrated in normal and immunocompromised animal models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for systemic infections due to Candida albicans. In common with other azole antifungal agents, most fungi show a higher apparent sensitivity to Fluconazole in vivo than in vitro. Fluconazole administered orally and/or intravenously was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Activity has been demonstrated against fungal infections caused by Aspergillus flavus and Aspergillus fumigatus in normal mice. Fluconazole has also been shown to be active in animal models of endemic mycoses, including one model of Blastomyces dermatitidis pulmonary infections in normal mice; one model of Coccidioides immitis intracranial infections in normal mice; and several models of Histoplasma capsulatum pulmonary infection in normal and immunosuppressed mice. The clinical significance of results obtained in these studies is unknown. Oral Fluconazole has been shown to be active in an animal model of vaginal candidiasis. Concurrent administration of Fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cr. neoformans, and antagonism of the two drugs in systemic infection with Asp. fumigatus. The clinical significance of results obtained in these studies is unknown. There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to Fluconazole (e.g., Candida krusei). Such cases may require alternative antifungal therapy. Return to top