The pharmacokinetics of itraconazole, an orally effective, broad-spectrum, systemic antifungal agent, were evaluated in five healthy male volunteers. Each subject was studied on days 1 and 15 at the following dosages: 100 mg once daily (regimen A), 200 mg once daily (regimen B), and 200 mg twice daily (regimen C). On each study day, itraconazole was administered with a standardized meal. Plasma samples were collected for 72 h postdose, and 24-h urine specimens were obtained. On day 1 of regimen C, plasma samples were collected following the second dose. Samples were assayed for itraconazole by a sensitive, reverse-phase, highperformance liquid chromatography method. Wide intersubject variations in itraconazole concentration in plasma versus time profiles were observed on all study days. Absorption appeared to be slow, with day 1 mean peak itraconazole concentrations in plasma of 110 ng/mI at 2.8 h (regimen A), 272 ng/ml at 3.0 h (regimen B), and 553 ng/ml at 3.4 h (regimen C). Mean peak itraconazole concentrations in plasma on day 15 were 412 ng/ ml at 3.0 h (regimen A), 1,070 ng/ml at 4.4 h (regimen B), and 1,980 ng/ml at 6.0 h (regimen C). The steady state was achieved by day 13. Respective elimination half-lives on days 1 and 15 were 15 and 34 h (regimen A), 20.7, and 36.5 h (regimen B), and 25 and 41.7 h (regimen C), respectively. The areas under the plasma concentration versus time curves (0 to infinity) on day 1 were 1,320 (regimen A), 4,160 (regimen B), and 12,600 ng -h/ml (regimen C) . On day 15, the areas under the plasma concentration versus time curves (0 to 24 h) were 5,330 (regimen A), 15,400 (regimen B), and 39,300 ng-h/ml (regimen C). With the exception of one patient on day 15 of regimen C, itraconazole was not detected in the urine. All data support dose-dependent pharmacokinetic behavior for itraconazole.

Eight patients with systemic mycoses and with prior treatment failures were treated with itraconazole (600 mg/day) for a mean duration of 5.5 months. All six patients without AIDS experienced improvement or stabilization of their fungal infections while receiving high-dose itraconazole, although two patients later experienced treatment failures, one by relapse and one by progression, on lower doses. Treatment failures also occurred in the two patients with AIDS and cryptococcal meningitis. The failures were associated with low serum itraconazole concentrations (<2.5 ,ug/ml) in both patients. All other patients had mean trough levels in serum above 5 ,ug/ml. One patient who was improving on 600 mg/day developed a progressive infection after reduction of the dose to 400 mg/day. Side effects included reversible adrenal insufficiency in one patient; severe hypokalemia, mild diastolic hypertension, and rhabdomyolysis in one patient; mild hypokalemia and hypertension in four other patients; and breast tenderness in one patient. The mean decrease in serum potassium during treatment was statistically significant (P = 0.05). Selected patients with severe systemic mycoses may benefit from prolonged high-dose itraconazole treatment. However, 600 mg/day may be approaching the upper limits of acceptable dosing for long-term treatment.

Itraconazole is a triazole with a mechanism of action similar to that of ketoconazole. Endocrine side effects of ketoconazole, including impaired cortisol synthesis, have been well documented (A. Pont, J. R. Graybill, P. C. Craven, J. N. Galgiani, W. E. Dismukes, R. E. Reitz, and D. A. Stevens, Arch. Intern. Med. 144:2150Med. 144: -2153Med. 144: , 1984. We examined the adrenal response to corticotropin in 10 patients being treated with itraconazole. No impairment of cortisol synthesis could be demonstrated.Itraconazole (R 51,211) is a broad-spectrum oral antifungal agent currently undergoing clinical trials in both dermatophyte infections and the systemic mycoses. This compound shares structural similarities with the imidazole derivative ketoconazole (5). Furthermore, the drugs are believed to have similar mechanisms of action (19).Ketoconazole was first recognized to have endocrine side effects when some patients receiving the drug developed gynecomastia (3). Further studies demonstrated interference of ketoconazole with androgen (6,12,14,15), estrogen (10,20), and glucocorticoid synthesis (9, 13). Studies of steroidogenesis in cultured mouse adrenal cortex tumor cells indicate that ketoconazole directly inhibits 1-hydroxylase activity (7). There are only a few reports in which clinically significant hypoadrenalism has been attributed to ketoconazole therapy (17,18,21). The similarities between itraconazole and ketoconazole prompted us to study the adrenal response to corticotropin in patients receiving itraconazole therapy for a variety of mycotic infections.Of 10 patients referred for therapy of documented mycotic infections, 6 had coccidioidomycosis and 1 each had mucocutaneous candidiasis, aspergilloma, cutaneous sporotrichosis, and pulmonary cryptococcosis. A brief clinical outline of the patients studied is presented in Table 1.Several patients had received prior antifungal therapy, and five (patients no. 1, 2, 4, 6, and 7) had been treated with ketoconazole. None of the patients received concomitant antifungal agents during itraconazole therapy.Three additional patients (one each with aspergilloma, pulmonary coccidioidomycosis, and disseminated coccidioidomycosis) who completed baseline adrenal testing before itraconazole therapy did not consent to follow-up corticotropin studies.The 1-h corticotropin stimulation tests were performed as previously described (1). The 8-h tests were conducted with a continuous 8-h infusion of corticotropin (cosyntropin; 400 p.g in 500 ml of 5% glucose in water

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