Biological matrix-dependent pharmacokinetic and pharmacodynamic parameters of a novel platelet glycoprotein IIB/IIIA receptor antagonist, XU063, in beagle dogs.
The pharmacokinetic-pharmacodynamic (PK/PD) relationship of a novel platelet glycoprotein IIb/IIIa receptor antagonist, XU063, was evaluated as a function of biological matrix in beagle dogs. The disposition of 14C-radioactivity in various blood or plasma matrices and kinetics of inhibition of adenosine diphosphate (ADP) induced platelet aggregation were determined in beagle dogs following an intravenous infusion of 14C-XU063 at 2 micrograms/kg for 45 min. The 14C-radioactivity was maximum in platelet poor plasma (PPP) harvested from blood collected in EDTA and lowest in PPP harvested from blood collected in citrated vacutainers over the entire concentration versus time profile during and post infusion. The 14C-radioactivity values in blood and platelet rich plasma (PRP) were comparable and were between EDTA PPP and citrated PPP values. The resultant estimates of the PK and PD parameters of 14C-XU063 varied widely depending on the type of matrix used. The systemic clearance values for 14C-XU063 were 1 and 10 mL/min/kg for EDTA and citrated PPP, respectively. The values for the volume of distribution at steady-state were 0.2 and 1.3 L/kg, for EDTA and citrated PPP, respectively. The terminal elimination half-life appeared independent of the matrix 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 ng/mL (EDTA PPP, total drug). These results demonstrated the dependence of PK and PD parameters of antiplatelet agent XU063 on the type of biological matrix used to determine concentrations of XU063. The pros and cons of various blood sample collection methods for the evaluation of PK/PD relationship of potential antiplatelet agents are presented.
Kapil
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RP
Drug Metabolism and Pharmacokinetics Section, Stine-Haskell Research Center, DuPont Merck Pharmaceutical Company, Newark, DE 19714, USA. kapilrp@A1.lldmpc.umc.dupont.com
Emm
T A
TA
Mousa
S A
SA
Padovani
P K
PK
Quon
C Y
CY
Lam
G N
GN
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001774:Blood Chemical Analysis / Q000379:methods; D001798:Blood Proteins / Q000378:metabolism; D001800:Blood Specimen Collection / Q000379:methods; D004285:Dogs; D006207:Half-Life; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008657:Metabolic Clearance Rate; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011485:Protein Binding
D001798:Blood Proteins; D007555:Isoxazoles; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C107137:XU 063; D000244:Adenosine Diphosphate