Compartmental pharmacokinetics and tissue distribution of the antifungal triazole ravuconazole following intravenous administration of its di-lysine phosphoester prodrug (BMS-379224) in rabbits.
OBJECTIVE
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 (i.v.) 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 i.v. 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, AUC(0-infinity), V(ss), CL and terminal half-life (means +/- SEM) ranged from 2.03 to 58.82 mg/L, 5.80 to 234.21 mg x 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 AUC(0-infinity) (from 2.40-3.01 up to 11.90 and 14.56 mg x h/L; P = 0.0382). Tissue concentrations 30 min after the last dose were highest in the liver (12.91-562.68 microg/g), adipose tissue (10.57-938.55 microg/g), lung (5.46-219.12 microg/g), kidney (3.95-252.44 microg/g) and brain tissue (2.37-144.85 microg/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.
Groll
Andreas H
AH
Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, CRTC-1-575, Bethesda, MD 20892, USA.
Mickiene
Diana
D
Petraitis
Vidmantas
V
Petraitiene
Ruta
R
Kelaher
Amy
A
Sarafandi
Alia
A
Wuerthwein
Gudrun
G
Bacher
John
J
Walsh
Thomas J
TJ
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D006207:Half-Life; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008239:Lysine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011817:Rabbits; D013844:Thiazoles / Q000008:administration & dosage* / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014230:Triazoles / Q000008:administration & dosage* / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*
C508093:BMS-379224; D011355:Prodrugs; D013844:Thiazoles; D014230:Triazoles; C104066:ER 30346; D008239:Lysine