ITRACONAZOLE

Itraconazole is preferred to ketoconazole for most fungal infections in people because of its increased activity and decreased adverse effects.¹⁶ It is available as 100-mg capsules and as a suspension (10 mg/ml). The capsules contain beads coated with itraconazole, which facilitates drug absorption from the intestines. The use of compounded itraconazole from bulk chemical is not recommended because of its low solubility and poor stability. The commercially available formulations of itraconazole are incorporated into a hydroxypropyl-beta-cyclodextrin carrier, so the bulk compounded formulations are not equivalent. Reformulating the capsules into smaller doses has been successful, but the beads must remain intact. The cost of itraconazole for a 44-lb dog (5 mg/kg orally once a day) is about $8/day.

Potential indications

Itraconazole's activity against Sporothrix schenckii is variable but itraconazole is considered the treatment of choice. In comparison to itraconazole, terbinafine, which is discussed in more detail later, has greater in vitro potency as well as demonstrated successful treatment of clinical cases in people.^18,19

Pharmacokinetics

Itraconazole is highly protein-bound (> 99%) but is well-distributed throughout the body. It accumulates in skin, liver, fat, and the adrenal medulla. Itraconazole does not reach minimum inhibitory concentrations in the cerebrospinal fluid, but it has been effective in experimental models of CNS disease and in cats with Cryptococcus species CNS infections.¹ In dogs, itraconazole is metabolized in part to hydroxyitraconazole, which has antifungal activity similar to that of the parent compound.

Itraconazole is variably absorbed after oral administration in dogs and cats.^20,21 In dogs, itraconazole absorption is above 90% when capsules are administered with food compared with about 40% absorption in fasted patients. In fasted cats, itraconazole solution is about 70% absorbed.²¹

Itraconazole is primarily eliminated by hepatic metabolism and biliary secretion, with less than 1% of the drug eliminated by renal mechanisms.²⁰ The half-life in dogs and cats is 28 to 30 hours after a single dose. The half-life increases with multiple doses. Itraconazole is highly lipophilic, so concentrations in tissues persist longer than plasma concentrations. As a result of itraconazole accumulation in tissue such as the stratum corneum, pulse dosing has been effective in treating Malassezia dermatitis in dogs (5 mg/kg orally once a day for two days, repeated weekly for three weeks) and dermatophyte infections in cats (5 to 10 mg/kg orally once a day for seven days, then alternating one week on, one week off until a cure is achieved).²² However, systemic treatment with itraconazole as a sole treatment for Malassezia otitis has resulted in poor responses, and adjunctive treatments, such as topical medications, are suggested.²²

Drug interactions and adverse effects

Itraconazole appears to be better tolerated than ketoconazole in dogs and cats. Itraconazole can result in nausea, vomiting, and anorexia, but these signs may occur less frequently and appear to be dose-dependent.²³ Hepatotoxicosis may occur in as many as 10% of dogs receiving long-term treatment with itraconazole.²³ As with ketoconazole, slight increases in liver enzyme activities can occur with itraconazole administration but are not indicative of hepatotoxicosis. The increases in liver enzyme activities appear to be correlated with increasing itraconazole plasma concentrations and dosages.^1,23 In contrast to ketoconazole, itraconazole has minimal effects on cortisol and testosterone concentrations.²⁴