Overview of Albaconazole


was effective in mice, rat and rabbit models of systemic candidiasis (C. albicans). Albaconazole dose-dependently reduced fungal load after five days of treatment in a mouse model of vaginitis induced by a fluconazole-resistant C. albicans strain.35


Both albaconazole and


fluconazole (5 mg/kg, twice daily [bid], orally [po]) significantly decreased kidney fungal burden as compared with placebo in systemically infected rats.36


In a model of systemic candidiasis in rabbits, albaconazole was more effective than fluconazole in reducing kidney and lung fungal burden.36


a rabbit model of cryptococcosis (Cryptococcus neoformans), albaconazole and fluconazole significantly decreased fungal burden in cerebral spinal fluid and increased survival.9


In a rat model of aspergillosis (A. fumigatus) albaconazole dose-dependently reduced hepatic fungal burden. At 50 mg/kg bid, po, it completely eradicated fungi from the liver.36


N F N Cl


Figure 1: Chemical Structure Me


N N OH N


O


F In a study using


in mice to 60 hours in dogs. The absolute bioavailability was 100 % in rats and dogs and 50–70 % in monkeys.4


In a rabbit model of


scedosporiosis (Scedosporium prolificans), albaconazole at 50 mg/kg po completely protected from mortality and eradicated fungal burden in spleen, liver and lung. Treatment with amphotericin B (0.8 mg/kg, intravenous [iv]) proved less effective.37


In a dog model of


trypanosomiasis, orally administered albaconazole at 1.5 mg/kg/day for 90 days showed higher trypanocidal activity than currently used benznidazole when animals were infected with a strain partially resistant to the drugs nifurtimox and benznidazole. In addition, albaconazole was very effective in suppressing the proliferation of the parasite in animals infected with the Berenice-78 T. cruzi strain.38


Toxicity The toxicity of albaconazole was studied in mice, rats, dogs and


monkeys. The median lethal dose (LD50) obtained for rats and mice was greater than 2,000 mg/kg po. Sub-chronic and chronic toxicity studies were performed in rats and monkeys. A 26-week toxicity study in rats (3, 30 and 300 mg/kg po) revealed no mortality in any of the groups in spite of the high systemic exposure to albaconazole. Main findings were observed mostly at the highest dose and included increases in liver and thyroid weight and thyroid hyperplasia. These effects are commonly seen with CYP3A4 inducers. Histopathological alterations reverted after a four-week recovery period. A 39-week toxicity study in cynomolgus monkeys (2, 10 and 50 mg/kg/day po) showed minor toxicity findings, including a dose-dependent decrease in cholesterol levels, mainly the low-density lipoprotein (LDL) fraction. Histopathological changes were observed in the livers and adrenals of the animals treated at 50 mg/kg. All alterations remitted after the four-week recovery period.


In vitro, albaconazole had no effect on action potential duration in isolated Purkinje fibres and negligible inhibition of the HERG channel. In vivo, the compound had no detectable effect on cardiovascular (including electrocardiograms [ECGs]), respiratory or haemodynamic parameters in dogs. Albaconazole did not show mutagenicity in the Ames test or clastogenic effects in the chromosome aberration analysis in human lymphocytes in vitro and in the micronucleus test in vivo. Two-year carcinogenicity studies in mice and rats are in progress. In pregnant rats and rabbits, albaconazole showed no significant mother toxicity or impaired embryofoetal development. Also, no peri- or post-natal toxicity was observed.


Pharmacokinetics In vitro, albaconazole was bound to human proteins in 95 %. Among the main human cytochromes, albaconazole inhibited CYP3A4 (half


maximal inhibitory concentration (IC50) = 2.3 μM using testosterone as substrate). In vivo pharmacokinetic studies were performed in mouse, rat, rabbit, dog and monkey.39


Half-life values ranged from one hour EUROPEAN INFECTIOUS DISEASE


The safety, tolerability and pharmacokinetics of an oral solution of albaconazole were studied in a total of 72 healthy volunteers participating in two studies. Subjects were administered either single (80, 160, 240, 320, 400, 600 or 800 mg) or multiple (80 or 160 mg/day for 14 days) doses. Good tolerability was reported. In the multiple dose study, the most frequent adverse events (AEs) were mild to moderate headache and abdominal pain. High drug exposure was detected after both single and multiple doses. After single doses, peak plasma


concentration (Cmax) values increased proportionally from approximately 1 to 8 μg/ml, but the increase in area under the curve (AUC) was greater than proportional. Albaconazole was characterised by little inter-subject variability in pharmacokinetic parameters, rapid absorption and


prolonged half-life (t1/2 = 55–93 hours). Plasma accumulation appeared to occur after repeated administration of high doses.40


A study with 24 male volunteers examined the interaction of albaconazole (80 mg, capsule) with CYP3A4 using simvastatin (40 mg). Single- and multiple-dose albaconazole increased both plasma


simvastatin and hydroxyacid simvastatin Cmax and AUC levels by five- to sevenfold.4


In a Phase 1 food interaction study, albaconazole (50 mg, capsules), administered under fed or fasted conditions, showed similar AUC values, indicative of no major interactions with food intake.41


The absorption, metabolism, pharmacokinetics and excretion of [14C]-albaconazole (80 mg, oral solution) were examined in a Phase 1


study involving six male volunteers. The Cmax values for radioactivity in plasma and whole blood were 1.2 and 0.7 μgEq/ml, respectively and the


mean t1/2 values for radioactivity in plasma and whole blood were 65 hours and 71 hours, respectively. The unchanged drug was the major component detected in plasma together with very low concentrations of three metabolites. Albaconazole was rapidly absorbed and well distributed to tissues, with bi-exponential decay and long half-life


89 In vitro studies of metabolism


using hepatocytes from different species identified five different metabolites. The main metabolite in man, both in vitro and in vivo, was identified by total synthesis as 6-hydroxyalbaconazole, a compound one order of magnitude less active in vitro than the parent drug. Systemic exposure to this metabolite in humans was low. 6-hydroxyalbaconazole is not a CYP3A4 inhibitor, it is non-mutagenic and it has no activity in the HERG channel up to 10 μM.


Clinical Studies


Albaconazole has been assayed in several clinical trials, including three Phase 2 studies in vulvovaginal candidiasis, tinea pedis and toenail onychomycosis.


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