title: Itraconazole IV nanosuspension enhances efficacy through altered pharmacokinetics in the rat.
abstract: The goal of this research was to evaluate an intravenous itraconazole nanosuspension dosage form, relative to a solution formulation, in the rat. Itraconazole was formulated as a nanosuspension by a tandem process of microcrystallization followed by homogenization. Acute toxicity, pharmacokinetics, and distribution were studied in the rat, and compared with a solution formulation of itraconazole. Efficacy was studied in an immunocompromised rat model, challenged with a lethal dose of either itraconazole-sensitive or itraconazole-resistant C. albicans. Itraconazole nanosuspension was tolerated at significantly higher doses compared with a solution formulation. Pharmacokinetics of the nanosuspension were altered relative to the solution formulation. C(max) was reduced and t(1/2) was much prolonged. This occurred due to distribution of the nanosuspension to organs of the monocyte phagocytic system (MPS), followed by sustained release from this IV depot. The higher dosing of the drug, enabled in the case of the nanosuspension, led to higher kidney drug levels and reduced colony counts. Survival was also shown to be superior relative to the solution formulation. Thus, formulation of itraconazole as a nanosuspension enhances efficacy of this antifungal agent relative to a solution formulation, because of altered pharmacokinetics, leading to increased tolerability, permitting higher dosing and resultant tissue drug levels.
authors.affiliation: Baxter Pharmaceuticals and Technologies, Baxter Healthcare Corporation, Baxter Technology Park, Route 120 and Wilson Road, Round Lake, IL 60073, USA. barrett_rabinow@baxter.com
authors.forename: Barrett
authors.initials: B
authors.lastname: Rabinow
authors.forename: James
authors.initials: J
authors.lastname: Kipp
authors.forename: Pavlos
authors.initials: P
authors.lastname: Papadopoulos
authors.forename: Joseph
authors.initials: J
authors.lastname: Wong
authors.forename: Jill
authors.initials: J
authors.lastname: Glosson
authors.forename: Jerome
authors.initials: J
authors.lastname: Gass
authors.forename: Chong-Son
authors.initials: CS
authors.lastname: Sun
authors.forename: Todd
authors.initials: T
authors.lastname: Wielgos
authors.forename: Randy
authors.initials: R
authors.lastname: White
authors.forename: Chyung
authors.initials: C
authors.lastname: Cook
authors.forename: Kerry
authors.initials: K
authors.lastname: Barker
authors.forename: Kristy
authors.initials: K
authors.lastname: Wood
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage*; D002626:Chemistry, Pharmaceutical; D017964:Itraconazole / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013535:Suspensions; D014018:Tissue Distribution
chemical_list: D000935:Antifungal Agents; D013535:Suspensions; D017964:Itraconazole