Nonlinear binding models suggest that ABCIXIMAB (AB) Pharmacokinetics (PK) and pharmacodynamics (PD) are target-mediated

Abstract

We have previously developed a mechanism-based model that simultaneously characterizes the PK/PD properties of AB, a potent αIIbβ3 receptor antagonist, in patients undergoing coronary angioplasty. The model integrates the thermodynamics of drug-receptor binding with AB PK, assuming rapid equilibrium conditions and that free drug concentrations control the ex vivo inhibition of platelet aggregation (in the presence of 20μM adenosine diphosphate). The purpose of this paper is to further test the assumption of equilibrium binding conditions and to evaluate the PD implications of this model. Mean PK/PD data formerly used to construct the model were reanalyzed with a model utilizing drug-binding microconstants. Simulations of receptor occupancy and PK/PD profiles using several values of binding capacity (RT), affinity (KD), and drug sensitivity (EC50) were then conducted using a clinically relevant dosing regimen. Although both models reasonably described the data, receptor occupancy profiles were compared to experimental data and best characterized with the previous rapid equilibrium model. Whereas a 100-fold range of KD values had little effect on PK profiles, small increases in RT resulted in lower free drug concentrations and a shift in PD reflective of decreased potency, which is indirectly supported by clinical studies. Changes in EC50 also shifted PD curves as anticipated. Thus, we hypothesize that AB PK is target-mediated imposing clinically important PD consequences. Clinical Pharmacology & Therapeutics (2004) 75, P88–P88; doi: 10.1016/j.clpt.2003.11.338