JAC Advance Access published online on September 19, 2005
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dki287
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1 Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, CRTC-1-575, Bethesda, MD 20892, USA; Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Pediatric Hematology/Oncology, University Children's Hospital, Muenster, Germany
* To whom correspondence should be addressed. 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- 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.
Received March 17, 2005
Revised July 14, 2005
Accepted July 24, 2005
Original article
Compartmental pharmacokinetics and tissue distribution of the antifungal triazole ravuconazole following intravenous administration of its di-lysine phosphoester prodrug (BMS-379224) in rabbits
2 Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, CRTC-1-575, Bethesda, MD 20892, USA
3 Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Pediatric Hematology/Oncology, University Children's Hospital, Muenster, Germany
4 Surgery Service, Veterinary Resources Program, Office of Research Services, National Institutes of Health, Bethesda, MD, USA
Thomas J. Walsh, E-mail: walsht{at}mail.nih.gov
Abstract 
, 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).
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