Received for publication December 20, 2005.
Revised May 29, 2006.
Accepted for publication May 31, 2006.

Physiologically-based pharmacokinetic (PBPK) modelling of FTY720 in rats following oral and intravenous doses

Abstract

FTY720 is a new sphingosine-1-phosphate receptor agonist being developed for multiple sclerosis and prevention of solid organ transplant rejection. A physiologically based pharmacokinetic model was developed to predict the concentration of FTY720 in various organs of the body. Single oral and intravenous doses of FTY720 were administered to male Wistar rats, with blood and tissue sampling over 360 hours analyzed by LC/MS/MS. A well-stirred model (perfusion-rate limited) described FTY720 kinetics in heart, lungs, spleen, muscle, kidneys, bone and liver; a permeability rate limited model being required for brain, thymus and lymph nodes. Tissue-to-blood partition coefficients (R_T) ranged from 4.69 (muscle) to 41.4 (lungs). In lymph nodes and spleen, major sites for FTY720 induced changes in sequestration of lymphocytes, R_T were 22.9 and 34.7, respectively. Permeability-surface area products for brain, thymus and lymph nodes were 39.3, 122, and 176 mL/min. Intrinsic hepatic clearance was 23145 L/hr/kg for the free drug in blood (f_ub 0.000333); systemic clearance was 0.748 L/hr/kg and terminal half-life 23.4 hours. The fraction orally absorbed was 71%. The model characterized well FTY720 disposition for this extensive dosing and tissue collection study in the rat. On scaling the model to dogs and humans, good agreement was found between the actual and predicted blood concentration-time profiles. More importantly, brain concentrations in dogs were well predicted from the rat. In absolute terms the predictions were slightly lower than observed values, just under 1.5 fold deviation, but the model accurately predicted the terminal elimination of FTY720 from the brain.

Key words: kinetic modeling, pharmacokinetic modeling, pharmacokinetics, physiologically-based modeling, physiologically-based pharmacokinetics

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