Quasi-equilibrium pharmacokinetic model for drugs exhibiting target-mediated drug disposition

Purpose: The aim of this study is to derive and evaluate an equilibrium model of a previously developed general pharmacokinetic model for drugs exhibiting target-mediated drug disposition (TMDD). Methods: A quasi-equilibrium solution to the system of ordinary differential equations that describe the kinetics of TMDD was obtained. Computer simulations of the equilibrium model were carried out to generate plasma concentration-time profiles resulting from a large range of intravenous bolus doses. Additionally, the final model was fitted to previously published pharmacokinetic profiles of leukemia inhibitory factor (LIF), a cytokine that seems to exhibit TMDD, following intravenous administration of 12.5, 25, 100, 250, 500, or 750 mu g/kg in sheep. Results: Simulations show that pharmacokinetic profiles display steeper distribution phases for lower doses and similar terminal disposition phases, but with slight underestimation at early time points as theoretically expected. The final model well-described LIF pharmacokinetics, and the final parameters, which were estimated with relatively good precision, were in good agreement with literature values. Conclusions: An equilibrium model of TMDD is developed that recapitulates the essential features of the full general model and eliminates the need for estimating drug-binding microconstants that are often difficult or impossible to identify from typical in vivo pharmacokinetic data.