Abstract
793 FTY 720 is a new immunosuppressant compound for use in organ transplantation. FTY 720 alters lymphocyte trafficking in peripheral blood resulting in a reversible, dose-dependent lymphopenia by an unknown mechanism of action. In this preliminary report on the first in human trial of this compound, the relationship between FTY 720 blood concentration and lymphopenic effect is explored and modeled. Methods. Absolute lymphocyte count and whole blood FTY 720 concentration data collected over 96 hours post single oral dose of 0.25 mg to 1.0 mg in stable renal transplant patients were used to construct an indirect PK-PD model. Sequential fitting of the PK data with a one compartment model and first order elimination as well as first order absorption was initially performed. Individual (bayesian) PK parameters were then used to produce a concentration-time profile for fitting the PD model. The PD model consists of a lymphocyte pool originally at steady state with zero order input and first order elimination with modulation of both the input and the elimination of lymphocytes by the concentrations in the central and effect compartments. Results. The PK and PD model parameter estimates are listed. Ka-absorption constant, Vc-volume of the central compartment, Ke-elimination constant, Keo-elimination from the effect compartment and Lin-base formation and elimination rate of lymphocytes. (Table)TableCV%*-interindividual variability. Conclusions. FTY 720 manifests characteristics of a one compartment model with first order elimination with high interindividual variability in the absorption process. Modulation of input for lymphocyte count was dependent on the concentration in the central compartment while the return to baseline was effected by the concentration in the effect compartment (based on Keo). Simulations will be tested against multiple dose studies to validate the model and to assist in understanding the variability of the drug in larger populations.
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