Analysis of drug-receptor interactions in vivo: a new approach in pharmacokinetic-pharmacodynamic modelling.

Analysis of pharmacodynamic data using the empirical Hill equation only provides limited insights in the underlying factors that determine the shape and location of a concentration-effect curve, such as agonist affinity and efficacy. We have developed a method which allows for the estimation of agonist affinity and efficacy in vivo and yields more insight in the factors that determine pharmacodynamic variability. The method is based on the "operational model of agonism", which describes agonist concentration-effect curves in terms of the maximum system effect (Em), the slope of the transducer function (n), the agonist dissociation equilibrium constant (KA) and an efficacy parameter (tau). We applied the model to obtain estimates of apparent affinity and efficacy of a series of N6-cyclopentyladenosine (CPA) analogues for adenosine A, receptor-mediated in vivo effects on heart rate in rat [Van der Graaf et al. 1997]. In all cases, the model converged and estimates of apparent affinity (pKA) and efficacy (tau) were obtained which were highly consistent with results from in vitro radioligand-binding studies. In conclusion, we have shown that the operational model of agonism can provide meaningful measures of agonist affinity and efficacy in vivo. The model may serve as a practical guide for future development of partial adenosine A1 receptor agonists and help to elucidate the mechanisms underlying adenosine A1 receptor-mediated responses in vivo.