Clinical Pharmacokinetics of Systemic Antifungal Drugs

Abstract

The currently available drugs for the treatment of systemic fungal infections are amphotericin B. flucytosine. miconazole and ketoconazole.Amphotericin B has to be given intravenously in the treatment of deep mycoses. The dose is gradually increased following a small initial dose. though this may delay the attail/menl of therapeutic concentrations. Amphotericin B. serum concentrations are proportiol/al to dose but only up to doses of 50mg. The serum pharmacokinetics fit a 3-compartment model. while cerebrospinal fluid pharmacokinetics fit a 2-compartment model. The precise identities of these compartments have not been determined. In the serum there is a relatively rapid initial half-life of 1 to 2 days. and a slower elimination phase of 15 days. Amphotericin B penetrates poorly into other body tissues. and concentrations are usually well below those in serum. This may partly be due to its high protein binding. The routes of amphotericin B elimination in man are unknown. Amphotericin B invariably causes doserelated renal damage. but this does not markedly alter its pharmacokinetics; mannitol infusions do not reduce this nephrotoxicity. Concurrent gentamicin administration and sodium depletion may enhance amphotericin B nephrotoxicity.Flucytosine may be given orally or intravenously. It has a high (greater than 80%) oral bioavailability. but this is lower in patients with renal failure. Flucytosine absorption is delayed in renal failure and by antacids. The serum pharmacokinetics fit a I-compartment model. and the apparent volume of distribution approximates to body water. Flucytosine has low protein binding and good tissue penetration. There is minimal metabolism in man; conversion to 5-fluorouracil may be the basis of flucytosine toxicity. Since flucytosine is largely eliminated by renal excretion. serum concentrations are markedly increased in the presence of renal impairment. The renal clearance of flucytosine closely parallels creatinine clearance. and in renal failure the half-life is considerably prolonged. Toxicity can be avoided by therapeutic monitoring of serum concentrations and reducing the dose when renal functiol/ is impaired.Miconazole is poorly absorbed from the gut; therefore intravenous administration is required for treatment of systemic fungal infections. Its serum pharmacokinetics fit a 3-compartment model with a short initial half-life of less than 1 hour. an intermediate half-life of 2 hours. and a terminal half-life of 20 hours. Despite this long terminal half-life. miconazole has to be given every 8 hours. It has a high apparent volume of distribution and is highly bound to plasma proteins. Adequate penetration only occurs into certain body tissues. Pen-

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

“…Glucuronidation has not been reported for this drug and this could explain the lack of interaction. However, we also demonstrated that miconazole is a strong inhibitor of ZDV glucuronidation and glucuronides have not been described for this drug [16]. Miconazole could therefore interact with UGT by an unknown mechanism (formation of inactive complex, steric hindrance, physical or chemical perturbation of the microsomal membrane, etc).…”

Pharmacokinetic evaluation of UK-49,858, a metabolically stable triazole antifungal drug, in animals and humans

“…This is in contrast to the imidazole antifungal agents, including ketoconazole, in which plasma protein binding is typically in excess of 98% (4). This 40-to 50-fold difference in unbound fractions of UK-49,858 and ketoconazole in plasma is likely to be a significant contributory factor to the 20-to 100-fold potency advantage of UK-49,858 in vivo over ketoconazole (14; Troke et al, submitted).…”

“…Peak concentrations in plasma of drug normalized to a 1-mg/kg dose level following oral administration, were relatively high: 0.7, 0.6, 1.1, and 1. 4 ,ug/ml in mice, rats, dogs, and humans, respectively. The volumes of distribution ranged between 1.1 liter/kg in mice and 0.7 liter/kg in humans, which are approximate to the values for total body water.…”

“…The recent introduction of ketoconazole (1) has seen the advent of imidazole antifungal drugs with good systemic bioavailability and relatively high plasma concentrations. However, in common with previous imidazoles, ketoconazole is highly bound to plasma proteins (4,11), is extensively metabolized (9), and exhibits dose-dependent kinetics in both animals (1) and humans (2,5). This report describes the pharmacokinetic profile of the bistriazole UK-49,858, which is markedly different from that of ketoconazole and related imidazoles and assesses the potential contribution of this profile to the efficacy of the drug in vivo.…”

Effects of single and multiple doses of ketoconazole on adrenal function in normal subjects.

“…. Dosage could well be an important factor since there is evidence of dose-dependant kinetics for ketoconazole (Daneshmend & Warnock, 1983) and thus the potential exists for non-linear accumulation of drug with increasing dose and disproportionate effects on steroid synthesis. Preliminary data suggests that plasma cortisol concentrations may be greatly depressed throughout the day in occasional patients taking high doses of ketoconazole (Pont et al, 1983) although only one case has been reported of a patient receiving ketoconazole manifesting hypoadrenalism (discussed by Pont et al, 1984).…”