This study developed the pharmacokinetic (PK)ââ?¬â??pharmacodynamic (PD) model of the\ntestosterone-suppressive effect of leuprolide for evaluation of the sustained release (SR) depot and\nleuprolide solution in rats with or without prostate cancer. Six groups of rats were divided by the\nroutes of administration (intravenous and subcutaneous injection) and kinds of formulation (vehicle,\nleuprolide solution, and SR depot). The PK profile after subcutaneous injection of leuprolide solution\ncould be well-described by the one-compartment model. The absorption rate constant, the total body\nclearance, and the volume of distribution were estimated at 16.67 hâË?â??1, 514.46 mL/h, and 487.40 mL.\nUsing PK parameters in the solution-administered group, the PK model for the SR depot was\ndeveloped. The PKââ?¬â??PD model was constructed by describing the testosterone-suppressive effect of\nleuprolide using the feedback turnover model. The response of testosterone after administration of\neach formulation was well described using this PKââ?¬â??PD model for the estimation of PD parameters\n(EC50, Emax, h) and systemic parameters (kin, kout, kf on, kf off). The developed PKââ?¬â??PD model containing\nan inhibitory feedback system could successfully describe the testosterone-suppressive effect of\nleuprolide in the type of formulation. The PKââ?¬â??PD model developed would be useful for evaluating\nthe formulation of similar drugs whose effect is regulated through the feedback mechanism.
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