Pharmacokinetics of Intravenous Itraconazole followed by Itraconazole Oral Solution in Patients with Human Immunodeficiency Virus Infection

This randomized, open‐label, comparative study assessed the pharmacokinetics and safety of intravenous and oral hydroxypropyl‐β‐cyclodextrin (HP‐β‐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 daily for 2 days, then once daily for 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‐β‐CD in both intravenous and oral solutions, so HP‐β‐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 1690 ng/ml, respectively. During oral dosing, mean trough plasma concentrations of itraconazole and hydroxyitraconazole were maintained or increased in the 200 mg twice‐daily group but fell with the 200 mg once‐daily oral dose. Itraconazole was generally well tolerated and had a favorable safety profile; minor changes in hematology variables werenoted duringthe intravenous phase, and HP‐β‐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 a mean 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.