A PHARMACOKINETIC STUDY OF INTRAVENOUS ITRACONAZOLE FOLLOWED BY ORAL-ADMINISTRATION OF ITRACONAZOLE CAPSULES IN PATIENTS WITH ADVANCED HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION

A randomized, open-label, comparative study was conducted in 30 male p atients with moderately advanced human immunodeficiency virus (HIV) in fection to examine the pharmacokinetics of an investigational intraven ous preparation of itraconazole compared with pharmacokinetics after a dministration of itraconazole capsules. The study also assessed whethe r adequate plasma concentrations of itraconazole could be rapidly achi eved with the intravenous formulation and then maintained after cessat ion of intravenous therapy with itraconazole capsules. All patients re ceived 200 mg intravenous itraconazole as a 1-hour infusion in 40% hyd roxypropyl-beta-cyclodextrin (HP-beta-CD) vehicle twice daily for 2 da ys, and then 200 mg intravenously once daily for 5 days. Patients then received itraconazole capsules, either 200 mg twice daily or 200 mg o nce daily for 28 days. Steady-state plasma concentrations of itraconaz ole were reached by day 3 with intravenous infusion, a much shorter ti me than observed with administration of itraconazole capsules. Steady- state concentrations of itraconazole and hydroxyitraconazole were effe ctively maintained during the rest of the intravenous infusions of itr aconazole. Oral follow-up with administration of 200-mg capsules once daily could not maintain the plasma concentrations of itraconazole and hydroxyitraconazole obtained at the end of the intravenous treatment, whereas twice-daily oral administration maintained or increased these concentrations. Mean plasma concentrations of itraconazole and hydrox yitraconazole on day 7 were similar to those on day 36 in the twice-da ily group. Mean renal clearance was comparable to mean total body clea rance, and approximately 93% to 101% of the HP-beta-CD was excreted un changed in urine within 12 hours of administration. The HP-beta-CD was essentially eliminated through the kidney, and little accumulation in the body was observed in this patient population. Adverse events duri ng the intravenous phase were most commonly associated with intravenou s administration. Intravenous infusion of itraconazole for 7 days foll owed by administration of itraconazole capsules twice daily for 28 day s is an effective dose regimen in patients with advanced HIV infection . Journal of Clinical Pharmacology, 1998;38:593-602 (C)1998 The Americ an College of Clinical Pharmacology.