IngentaConnect Itraconazole: a treatment with pharmacokinetic foundations

Abstract:

Itrafungol^TMis a 10 mg/mL oral solution with the triazole itraconazole as active ingredient. It has recently been authorized in the UK, as a first country, for treatment of Microsporum canis dermatophytes in cats. The treatment schedule consisted of daily oral administration of 5 mg/kg body weight for three 1-week periods, with each week of treatment followed by a week without treatment (following a consecutive week-on, week-off schedule). This schedule was designed on the basis of data from pilot trials and was confirmed in two specific trials in naturally-infected cats. Clinical and mycological cures were monitored. In the second trial, plasma levels of itraconazole and its active metabolite, hydroxy-itraconazole, were also assayed. Itraconazole is a very lipophilic compound that is readily distributed to fat tissue and sebaceous glands. It is also keratinophilic and accumulates in the stratum corneum of the skin and in hairs. These properties make it readily available at the site of infection. Itraconazole is metabolized into many metabolites of which only hydroxy-itraconazole is antifungal. Plasma and hair levels of itraconazole and its active metabolite were determined in a separate trial in 24 cats after administration of Itrafungol^TMat the recommended treatment schedule. Samples were analysed by HPLC. Both compounds were rapidly detectable. Repeated administration for 1 week resulted in mean peak plasma levels of 1.05

g/mL at 1 h after the last dose of the week. Plasma concentrations dropped slowly during the week without treatment to around the quantification limit (5 ng/mL) just before the start of the second and third treatment periods. During these periods, there was a 20–30% increase of the 24-h plasma concentrations towards the end of these periods. Median concentration of itraconazole in hair samples of these cats was 0.168

g/g 24 h after the first dose. There was a clear increase of the median hair concentration after 1 week of treatment to 1.17

g/g. At the end of the second period, the median concentration was 2.00

g/g, and was 2.99

g/g at the end of the third period. At the end of each of the intermittent periods without treatment, hair concentrations dropped 25–30% to median values of 0.8–1.5

g/g. Two weeks after the last dose of the full treatment schedule, median hair concentrations were still 1.5

g/g. Although hair concentrations of hydroxy-itraconazole were below the quantification limit during the first and second treatment periods, they were quantifiable in an increasing number of hairs after the last period, with concentrations between 0.058 and 0.186

g/g. Concentrations of both compounds together, and even itraconazole alone, are well above the MIC₉₀for Microsporum canis strains (0.1

g/mL in various broth media) very shortly after the first dose and for up to 2 weeks after the last one. These data illustrate that the recommended treatment schedule (3 × 7 days of dosing) provides actual coverage of at least 7 weeks.

Funding: Janssen Animal Health.