BIOLOGICAL MATRIX-DEPENDENT PHARMACOKINETIC AND PHARMACODYNAMIC PARAMETERS OF A NOVEL PLATELET GLYCOPROTEIN IIB IIIA RECEPTOR ANTAGONIST, XU063, IN BEAGLE DOGS/

The pharmacokinetic-pharmacodynamic (PWPD) relationship of a novel pla telet glycoprotein IIb/IIIa receptor antagonist, XU063, was evaluated as a function of biological matrix in beagle dogs. The disposition of C-14-radioactivity in various blood or plasma matrices and kinetics of inhibition of adenosine diphosphate (ADP) induced platelet aggregatio n were determined in beagle dogs following an intravenous infusion of C-14-XU063 at 2 mu g/kg for 45 min. The C-14-radioactivity was maximum in platelet poor plasma (PPP) harvested from blood collected in EDTA and lowest in PPP harvested from blood collected in citrated vacutaine rs over the entire concentration versus time profile during and post i nfusion. The C-14-radioactivity values in blood and platelet rich plas ma (PRP) were comparable and were between EDTA PPP and citrated PPP va lues. The resultant estimates of the PK and PD parameters of C-14-XU06 3 varied widely depending on the type of matrix used. The systemic cle arance values for C-14-XU063 were 1 and 10 mL/min/kg for EDTA and citr ated PPP, respectively. The values for the volume of distribution at s teady-state were 0.2 and 1.3 L/kg, for EDTA and citrated PPP, respecti vely. The terminal elimination half-life appeared independent of the m atrix with a median value of 2 h. The estimated ex vivo IC50 values of XU063 ranged from 0.4 ng/mL (citrated PPP, platelet free drug) to 7 n g/mL (EDTA PPP, total drug). These results demonstrated the dependence of PK and PD parameters of antiplatelet agent XU063 on the type of bi ological matrix used to determine concentrations of XU063. The pros an d cons of various blood sample collection methods for the evaluation o f PWPD relationship of potential antiplatelet agents are presented. (C ) 1997 Elsevier Science Ltd.