Clinical Pharmacokinetics of Fluconazole

Abstract

Fluconazole 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 (t1/2) 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 t1/2 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 t1/2 was shorter in children.(ABSTRACT TRUNCATED AT 400 WORDS)

Population pharmacokinetics of fluconazole given for secondary prevention of oropharyngeal candidiasis in HIV-positive patients

“…The mean population pharmacokinetic parameter estimates were in the same range as those already reported [14,15,16,17]. Although a previous study reported no e ect of BW on¯uconazole pharmacokinetics [16], in this study BW signi®cantly in¯uenced¯uconaz-ole CL and V d .…”

Comparative effects of antifungal agents on zidovudine glucuronidation by human liver microsomes.

“…However, interactions occur at the hepatic enzyme level where in vivo drug concentrations are unknown. In the particular case of azole compounds, tissue concentrations are sometimes higher than plasma concentrations [15,19]. Nevertheless, microsomal fractions are only an in vitro model and in vitro results must be extrapolated with caution with regard to the effect of drugs on ZDV glucuronidation in vivo.…”

Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO

“…Fluconazole is highly reabsorbed in the renal tubule. For drugs that are reabsorbed, PK Sim requires an input for the fraction of tubular reabsorption by calculating the glomerular filtration rate (GFR) fraction as follows: $\text{GFR}\text{Fraction}=\frac{\text{Empiric}{\text{CL}}_{\mathrm{normalR}}}{\text{Expected}{\text{CL}}_{\mathrm{normalR}}}$where Empiric CL R equals the renal plasma clearance reported in the literature 23. Expected CL R is the renal plasma clearance expected due to GFR if there was no reabsorption or tubular secretion (expected CL R  = fraction unbound × GFR =  f u  × 110 mL/minute).…”

“…Metabolism was attributed to glucuronidation via UGT2B7, and unbound intrinsic clearance (${\text{CL}}_{\mathrm{normalI}}^{\prime }$) was calculated using hepatic clearance (CL H ) 24. The CL H was assumed to be 15% of total empiric clearance 23. A summary of the assumptions used in the model building process is included in Table S1.…”