A Pharmacokinetic Study of Intravenous Itraconazole Followed by Oral Administration of Itraconazole Capsules in Patients with Advanced Human Immunodeficiency Virus Infection

Abstract

A randomized, open-label, comparative study was conducted in 30 male patients with moderately advanced human immunodeficiency virus (HIV) infection to examine the pharmacokinetics of an investigational intravenous preparation of itraconazole compared with pharmacokinetics after administration of itraconazole capsules. The study also assessed whether adequate plasma concentrations of itraconazole could be rapidly achieved with the intravenous formulation and then maintained after cessation of intravenous therapy with itraconazole capsules. All patients received 200 mg intravenous itraconazole as a 1-hour infusion in 40% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) vehicle twice daily for 2 days, and then 200 mg intravenously once daily for 5 days. Patients then received itraconazole capsules, either 200 mg twice daily or 200 mg once daily for 28 days. Steady-state plasma concentrations of itraconazole were reached by day 3 with intravenous infusion, a much shorter time than observed with administration of itraconazole capsules. Steady-state concentrations of itraconazole and hydroxyitraconazole were effectively maintained during the rest of the intravenous infusions of itraconazole. 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 hydroxyitraconazole on day 7 were similar to those on day 36 in the twice-daily group. Mean renal clearance was comparable to mean total body clearance, and approximately 93% to 101% of the HP-beta-CD was excreted unchanged 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 during the intravenous phase were most commonly associated with intravenous administration. Intravenous infusion of itraconazole for 7 days followed by administration of itraconazole capsules twice daily for 28 days is an effective dose regimen in patients with advanced HIV infection.

Cyclodextrins

“…This may be related to its ability to interact with cellular membranes and its hemolytic activity (Thompson, 1997). The total plasma clearance for HP-β-CD and SBE-β-CD in all species tested is similar to the glomerular filtration rate of individual species (Davies and Morris, 1993), and essentially 100% of a given dose is recovered in the urine within 6 to 12 hours following IV administration (Zhou et al, 1998;CyDex, unpublished) Following absorption, CDs distribute to various tissues including the kidney, urinary bladder, liver, adrenal gland, and others (Gerloczy et al, 1990;Monbaliu et al, 1990;Antlsperger and Schmid, 1996;Kubota et al, 1996;De Bie et al, 1998;Van Ommen et al, 2004). The kidney has the highest level of CDs of all tissues.…”

Pharmacokinetics of Itraconazole and Hydroxyitraconazole in Healthy Subjects after Single and Multiple Doses of a Novel Formulation

“…However, the presence of large amounts of HPBCD can limit the use of higher doses, even though the dextrin compound is readily eliminated (26) and can be dialyzed (15). This led to the exploration for an alternative parenteral formulation of itraconazole in which larger crystals of the drug substance were milled in the surfactant pluronic F108, generating physically stable dispersions consisting of medium-size crystals (i.e., 50% were Ͻ200 nm and 90% were Ͻ335 nm).…”

Activities of an Intravenous Formulation of Itraconazole in Experimental DisseminatedAspergillus,Candida, andCryptococcusInfections

“…formulation of itraconazole solubilized in hydroxypropyl-␤-cyclodextrin (HPBCD) has successfully undergone clinical evaluation (11,19,21) and has recently been approved for clinical use. i.v.…”