Journal Article

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

Andreas H. Groll, Diana Mickiene, Vidmantas Petraitis, Ruta Petraitiene, Amy Kelaher, Alia Sarafandi, Gudrun Wuerthwein, John Bacher and Thomas J. Walsh

in Journal of Antimicrobial Chemotherapy

Published on behalf of British Society for Antimicrobial Chemotherapy

Volume 56, issue 5, pages 899-907
Published in print November 2005 | ISSN: 0305-7453
Published online September 2005 | e-ISSN: 1460-2091 | DOI: http://dx.doi.org/10.1093/jac/dki287
Compartmental pharmacokinetics and tissue distribution of the antifungal triazole ravuconazole following intravenous administration of its di-lysine phosphoester prodrug (BMS-379224) in rabbits

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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.

Keywords: mycoses; chemotherapy; drug development

Journal Article.  5463 words.  Illustrated.

Subjects: Medical Oncology ; Critical Care

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