title: Pharmacokinetics of intravenous itraconazole followed by itraconazole oral solution in patients with human immunodeficiency virus infection.
abstract: This randomized, open-label, comparative study assessed the pharmacokinetics and safety of intravenous and oral hydroxypropyl-beta-cyclodextrin (HP-beta-CD) solutions of itraconazole in patients with advanced human immunodeficiency virus (HIV) infection. All patients received 1-hour intravenous infusions of itraconazole 200 mg twice dailyfor 2 days, then once dailyfor 5 days. Patients were then randomized to receive itraconazole oral solution, 200 mg twice daily or 200 mg once daily, for a further 28 days. Itraconazole was solubilized by HP-beta-CD in both intravenous and oral solutions, so HP-beta-CD concentration in plasma was measured. Thirty-two patients were enrolled and analyzed (n = 32 for intravenous treatment, 32 completed; n = 16 for oral once daily, 15 completed; n = 16 for oral twice daily, 12 completed). Steady-state plasma concentrations of itraconazole and hydroxyitraconazole were reached by days 3 and 6, respectively. After intravenous dosing, mean trough plasma concentrations of itraconazole and hydroxyitraconazole were 906 ng/ml and 1,690 ng/ml, respectively. During oral dosing, mean trough plasma concentrations of itraconazole and hydroxyitraconazole were maintained or increased in the 200 mg twice-dailygroup but fell with the 200 mg once-daily oral dose. Itraconazole was generally well tolerated and had a favorable safetyprofile; minor changes in hematology variables were noted during the intravenous phase, and HP-beta-CD was cleared rapidly, mostly in urine. Twenty-eight patients (88%) experienced at least one adverse event; no adverse event was severe, and only seven were definitely related to itraconazole. In conclusion, itraconazole 200 mg given intravenously twice daily for 2 days, then once daily for 5 days, rapidly achieves amean steady-state trough concentration of itraconazole of over 250 ng/ml, which is associated with clinic outcome and is effectively maintained with itraconazole oral solution 200 mg twice daily in patients with advanced HIV infection.
authors.affiliation: Janssen Research Foundation, Titusville, New Jersey 08560-0200, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhao
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.forename: L
authors.initials: L
authors.lastname: Pesco-Koplowitz
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000284:Administration, Oral; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D003505:Cyclodextrins; D005260:Female; D015658:HIV Infections / Q000378:metabolism*; D006801:Humans; D007275:Injections, Intravenous; D017964:Itraconazole / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D047392:beta-Cyclodextrins
chemical_list: D000935:Antifungal Agents; D003505:Cyclodextrins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D017964:Itraconazole