JAC Advance Access originally published online on September 19, 2005
Journal of Antimicrobial Chemotherapy 2005 56(5):899-907; doi:10.1093/jac/dki287
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Published by Oxford University Press 2005
Compartmental pharmacokinetics and tissue distribution of the antifungal triazole ravuconazole following intravenous administration of its di-lysine phosphoester prodrug (BMS-379224) in rabbits
1 Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, CRTC-1-575, Bethesda, MD 20892, USA; 2 Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Pediatric Hematology/Oncology, University Children's Hospital, Muenster, Germany; 3 Surgery Service, Veterinary Resources Program, Office of Research Services, National Institutes of Health, Bethesda, MD, USA
Received 17 March 2005; returned 3 June 2005; revised 14 July 2005; accepted 24 July 2005
* Corresponding author. Tel: +1-301-402-0023; Fax: +1-301-480-2308; E-mail: walsht{at}mail.nih.gov
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
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