Optimisation of itraconazole therapy using target drug concentrations

Itraconazole is a new triazole compound with a broad spectrum of activity a gainst a number of fungal pathogens, including Aspergillus species. The dru g is being used increasingly as prophylaxis in patients with immunodepressi on, Itraconazole is highly lipophilic and only ionised at low pH, The absolute availability of capsules in healthy volunteers under fasting conditions is about 55% and is increased after a meal. Itraconazole is 99.8% bound to hum an plasma proteins and its apparent volume of distribution is about 11 L/kg . The drug is extensively metabolised by the liver. Among the metabolites, hydroxy-itraconazole is of particular interest because its antifungal activ ity measured in vitro is similar to that of the parent drug and its plasma concentration is 2 to 3 times higher than that of itraconazole. Mean total itraconazole blood clearance determined in healthy volunteers fo llowing a single intravenous infusion was 39.6 L/h, After a single oral dos e, the terminal elimination half-life of itraconazole is about 24 hours. Th e drug exhibits a dose-dependent pharmacokinetic behaviour. Renal failure does not affect the pharmacokinetic properties of itraconazol e; however, little is known about the effects of hepatic insufficiency. In immunocompromised patients the absorption of itraconazole is affected by ga strointestinal disorders caused by diseases and cytotoxic chemotherapy. The pharmacokinetics of itraconazole may be significantly altered when the drug is coadministered with certain other agents. Itraconazole is a potent inhibitor of cytochrome P450 (CYP) 3A4 and, thus, can also considerably cha nge the pharmacokinetics of other drugs. Such changes may have clinically r elevant consequences. Itraconazole appeals to be well tolerated. Gastrointestinal disturbances an d dizziness are the most frequently reported adverse effects. Clinical studies in patients with haemotological malignancies suggest that plasma concentrations [measured by high performance liquid chromatography ( HPLC)I greater than or equal to 250 mu g/L itraconazole, or 750 to 1000 mu g/L for itraconazole plus hydroxy-itraconazole, are required for effective prophylactic antifungal activity. It seems that a curative effect may be en hanced by ensuring that itraconazole plasma concentrations exceed 500 mu g/ L. The marked intra- and inter-patient variability in the pharmacokinetics of the drug, and the fact that it is impossible to predict steady-state plasma concentrations from the initial dosage are major factors obscuring any cle ar relationship between dose and plasma concentrations and clinical efficac y. Thus, in patients with life-threatening fungal infections treated with i traconazole drug, plasma concentrations should be regularly monitored to en sure sufficient drug exposure for antifungal activity.