Fluconazole - How It Works

CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism The pharmacokinetic properties (PK) 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.

Peak plasma concentrations (C max ) in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of approximately 30 hours (range: 20 to 50 hours) after oral administration.

In fasted normal volunteers, administration of a single oral 400 mg dose of fluconazole leads to a mean C max of 6.72 mcg/mL (range: 4.12 to 8.08 mcg/mL) and after single or multiple oral doses of 50 to 400 mg, fluconazole plasma concentrations and area under the plasma concentration-time curve (AUC) are dose proportional (Table 1).

The C max and AUC data from a food-effect study involving administration of fluconazole tablets to healthy volunteers under fasting conditions and with a high-fat meal indicated that exposure to the drug is not affected by food.

Therefore, fluconazole tablets may be taken without regard to meals. (See DOSAGE AND ADMINISTRATION .) Table 1: Mean Pharmacokinetic Parameters of Fluconazole in Adult Healthy Volunteers Following the Administration of Fluconazole Dose regimen C max (mcg/mL) AUC 0-24 (mcg*h/mL) Half-life (hours) 50 mg oral (once daily x 7 days) 2.21 37.6 26.6 100 mg oral (once daily x 7 days) 4.81 82.5 27.7 150 mg single oral 2.70 137* 34.1 200 mg oral (once daily x 14 days) 10.12 169.5 31 300 mg oral (once daily x 14 days) 15.98 299.4 34 400 mg oral (once daily x 14 days) 18.89 349.9 31 *AUC 0-inf.

C max = peak plasma concentrations, AUC =area under the plasma concentration time curve.

Steady-state concentrations are reached within 5 to 10 days following oral doses of 50 to 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% to 12%).

Following either single- or multiple oral doses for up to 14 days, fluconazole penetrates into all body fluids studied (see table below).

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 cerebrospinal fluid (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.

Table 2: Ratio of Fluconazole Tissue (Fluid)/Plasma Concentration Tissue or Fluid Ratio of Fluconazole Tissue (Fluid)/Plasma Concentration* Cerebrospinal fluid † 0.5 to 0.9 Saliva 1 Sputum 1 Blister fluid 1 Urine 10 Normal skin 10 Nails 1 Blister skin 2 Vaginal tissue 1 Vaginal fluid 0.4 to 0.7 * Relative to concurrent concentrations in plasma in subjects with normal renal function. † Independent of degree of meningeal inflammation.

Mean body clearance in adults is reported to be 0.23 (17%) mL/min/kg.