Compartmental pharmacokinetics and tissue distribution of the antifungal triazole ravuconazole following intravenous administration of its di-lysine phosphoester prodrug (BMS-379224) in rabbits

• Published in: Journal of antimicrobial chemotherapy 2005-11, Vol.56 (5), p.899-907
• Main Authors: Groll, Andreas H., Mickiene, Diana, Petraitis, Vidmantas, Petraitiene, Ruta, Kelaher, Amy, Sarafandi, Alia, Wuerthwein, Gudrun, Bacher, John, Walsh, Thomas J.
• Format: Article
• Language: English
• Subjects: Adipose Tissue - metabolism; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Brain - metabolism; chemotherapy; drug development; Half-Life; Injections, Intravenous; Kidney - metabolism; Liver - metabolism; Lung - metabolism; Lysine - administration & dosage; Lysine - analogs & derivatives; Lysine - pharmacokinetics; Medical sciences; mycoses; Pharmacology. Drug treatments; Prodrugs - administration & dosage; Prodrugs - pharmacokinetics; Rabbits; Thiazoles - administration & dosage; Thiazoles - analysis; Thiazoles - blood; Thiazoles - pharmacokinetics; Tissue Distribution; Triazoles - administration & dosage; Triazoles - analysis; Triazoles - blood; Triazoles - pharmacokinetics
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dki287

Objectives: Ravuconazole is a broad-spectrum antifungal triazole in clinical development. We investigated the compartmental plasma pharmacokinetics and tissue distribution of ravuconazole following administration of its novel intravenous (iv) di-lysine phosphoester prodrug, BMS-379224. Methods: Normal catheterized rabbits received the prodrug at 1.25, 2.5, 5, 10, 20 and 40 mg/kg once daily as 5 min iv bolus for 8 days. Serial plasma levels were collected at days 1 and 7, and tissues were obtained 30 min after the eighth dose. Concentrations of ravuconazole were determined by a validated HPLC method. Plasma concentration data were fitted to a three-compartment pharmacokinetic model. Pharmacokinetic parameters were estimated by weighted non-linear least squares regression analysis using the WinNonlin computer program. Results: Following single dosing, ravuconazole demonstrated linear plasma pharmacokinetics across the investigated dosage range. Cmax, AUC0–∞, Vss, CL and terminal half-life (means ± SEM) ranged from 2.03 to 58.82 mg/L, 5.80 to 234.21 mg · h/L, 5.16 to 6.43 L/kg, 0.25 to 0.18 L/h/kg and 20.55 to 26.34 h, respectively. Plasma data after multiple dosing revealed non-linear disposition at the 20 and 40 mg/kg dosage levels as evidenced by a dose-dependent decrease in CL (from 0.104–0.147 to 0.030 and 0.022 L/h/kg; P = 0.1053) and an increase in the dose-normalized AUC0–∞ (from 2.40–3.01 up to 11.90 and 14.56 mg · h/L; P = 0.0382). Tissue concentrations 30 min after the last dose were highest in the liver (12.91–562.68 μg/g), adipose tissue (10.57–938.55 μg/g), lung (5.46–219.12 μg/g), kidney (3.95–252.44 μg/g) and brain tissue (2.37–144.85 μg/g). Conclusions: The pharmacokinetics of ravuconazole fitted best to a three-compartment pharmacokinetic model. The compound revealed non-linear pharmacokinetics at higher dosages, indicating saturable clearance and/or protein binding. Ravuconazole displayed a long elimination half-life and achieved substantial plasma and tissue concentrations including in the brain.