Clinical Pharmacokinetics of Fluconazole

doi:10.2165/00003088-199324010-00002

Paper

Clinical Pharmacokinetics of Fluconazole

Published 1993 · D. Debruyne, J. Ryckelynck

Clinical Pharmacokinetics

Q1 SJR score

235

Citations

14

Influential Citations

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Abstract

SummaryFluconazole was recently developed for the treatment of superficial and systemic fungal infections. Triazole groups and insertion of 2 fluoride atoms increase the polarity and hydrosolubility of the drug, allowing it to be used in a parenteral form. Bioassay methods using Candida pseudotropicalis as a test organism were the first techniques used for the determination of fluconazole in body fluids. Gas chromatographic and high performance liquid chromatographic methods were later developed with better accuracy and sensitivity. Prediction of efficacious concentrations in patients from the minimum inhibitory concentrations in vitro seems to be uncertain because of low efficacy of the drug on some yeasts in vitro compared with efficacy in vivo in animal models.Oral forms (capsule and solution) are quickly absorbed and bioavailability is nearly complete (about 90%). Plasma protein binding is low (11 to 12%) and fluconazole circulates as active drug. Distribution is extensive throughout the tissues and allows the treatment of a variety of systemic fungal infections. The average elimination half-life (t½) of 31.6 ± 4.9h is long, with a minimum of 6 days needed to reach steady-state; thus, a loading dose (equal to double the maintenance dose) is recommended. The metabolism of fluconazole is not qualitatively or quantitatively significant. The main route of elimination is renal. The mean ± SD (calculated from published data) total and renal clearance values are 19.5 ± 4.7 and 14.7 ± 3.7 ml/min (1.17 ± 0.28 and 0.88 ± 0.22 L/h), respectively.Concentrations of fluconazole in blood after administration of single doses correlated well with the administered dose. There was very little interassay variation between the data reported in literature. Concentrations in blood after multiple doses also exhibit little variation and the accumulation factor was between 2.1 and 2.8. Fluconazole was found in many body fluids, especially in cerebrospinal fluid and dialysis fluid, allowing the treatment of systemic fungal infections such as coccidioidal meningitis and fungal peritonitis. Concentrations of 1 to 3 mg/L and 20 mg/L are the extreme values expected in clinical practice.In renal insufficiency the fluconazole t½ is longer, requiring dosage adjustment in relation to creatinine clearance. In continuous ambulatory peritoneal dialysis a 150mg dose in a 2L dialysis solution every 2 days has been proposed. In haemodialysis, a dose of 100 or 200mg should be given at the end of each dialysis session. Neither old age nor irradiation affect fluconazole pharmacokinetics, but the t½ was shorter in children. Antacid and melphalan did not modify fluconazole disposition but Cimetidine, diuretics and rifampicin produced significant changes in some fluconazole pharmacokinetic parameters. Fluconazole did not alter the pharmacokinetics of Phenazone (antipyrine) or of oral contraceptives but inhibited Phenytoin metabolism. The interaction of fluconazole with cyclosporin is not clearly established.

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Study Snapshot

Fluconazole effectively treats various fungal infections, with a long elimination half-life and extensive distribution throughout the body, making it a useful drug for treating various systemic fungal infections.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Clinical Pharmacokinetics of Fluconazole

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References

Fluconazole treatment of cutaneous cryptococcosis.

Fluconazole treatment effectively treated cutaneous cryptococcosis in a 58-year-old man with no history of trauma or fever.

Determination of fluconazole in human serum by solid-phase extraction and reversed-phase high-performance liquid chromatography.

This method provides a simple, rapid, and accurate method for measuring fluconazole in human serum, with a minimum detectable concentration of 0.1 microgram/ml.

Recalcitrant onychomycosis of the toenails successfully treated with fluconazole.

Fluconazole effectively treats recalcitrant onychomycosis of the toenails, providing a promising alternative to traditional treatments.

Contrasting effects of fluconazole and ketoconazole on phenytoin and testosterone disposition in man.

Fluconazole significantly increases phenytoin levels and increases testosterone concentrations in healthy male subjects, while ketoconazole has no significant effect on phenytoin levels.

Safety and pharmacokinetics of fluconazole in children with neoplastic diseases.

Fluconazole is safe and well-tolerated in children with neoplastic diseases, but its shorter serum half-life and higher frequency of aminotransferase elevations warrant further investigation in controlled clinical trials.

Stability of fluconazole and amino acids in parenteral nutrient solutions.

Fluconazole and amino acids in parenteral nutrient solutions are stable for up to two hours, with no visual evidence of incompatibility and no pH variations.

Fluconazole: a potent inhibitor of cytochrome P-450-dependent drug-metabolism in mice and humans in vivo. Comparative study with ketoconazole.

Fluconazole has a greater inhibitory effect on cytochrome P-450-dependent drug-metabolism in mice and humans than ketoconazole, but its plasma protein binding properties lead to a reversed order of inhibitory potencies for this enzyme system in vitro and in vivo.

A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation.

Fluconazole prophylactic administration reduces the incidence of both systemic and superficial fungal infections in patients undergoing bone marrow transplantation.

Citations

Parametric and nonparametric population pharmacokinetic analysis of fluconazole in critically ill patients and dosing simulations for Candida infections.

Higher loading doses may be necessary for fluconazole target achievement in critically ill patients, while using fluconazole for invasive C. glabrata infection should be discouraged due to poor PK/PD target attainment.

Therapeutic drug monitoring of antifungal therapies: do we really need it and what are the best practices?

Therapeutic Drug Monitoring (TDM) can optimize antifungal therapy and enhance treatment response, safety, and address altered pharmacokinetics in invasive fungal infection management.

Fluconazole-Induced Protein Changes in Osteogenic and Immune Metabolic Pathways of Dental Pulp Mesenchymal Stem Cells of Osteopetrosis Patients

Fluconazole shows potential as a treatment agent for CAII-deficient osteopetrosis patients by affecting proteins involved in osteogenesis and immune metabolic pathways.

In Vitro Impact of Fluconazole on Oral Microbial Communities, Bacterial Growth, and Biofilm Formation

Fluconazole can increase biofilm viability in oral microbiota, but may inhibit bacterial growth in non-fungal species, potentially disrupting biofilm communities.

Antimicrobial Peptide Synergies for Fighting Infectious Diseases

Combining antimicrobial peptides with other antimicrobial agents can enhance clinical outcomes, reduce toxicity, and prevent drug resistance in infectious diseases.

Pharmacokinetics and Bioequivalence of Fluconazole Capsules Manufactured in France and China in Healthy Chinese Participants: Open‐Label, Randomized, Single‐Dose, 2‐Way, Crossover Bioequivalence Study Under Fasted and Fed Conditions

The test fluconazole capsule was bioequivalent to the reference capsule and well-tolerated in healthy Chinese participants under fasted and fed conditions.

Azole antifungals and inter-individual differences in drug metabolism: the role of pharmacogenomics and precision medicine

Pharmacogenomics can potentially optimize the safety and effectiveness of azole antifungals, but its implementation in clinical practice remains inconclusive due to inconsistencies in dosing guidelines.