Pharmacokinetics and pharmacodynamics of argatroban in combination with a platelet glycoprotein IIB/IIIA receptor antagonist in patients undergoing percutaneous coronary intervention.
The pharmacokinetic-pharmacodynamic (PK-PD) relationship of argatroban, administered in combination with a platelet glycoprotein IIb/IIIa receptor antagonist, was characterized in patients undergoing percutaneous coronary intervention (PCI). Plasma argatroban and activated clotting times (ACTs) were assessed periprocedurally in 152 patients administered argatroban (250- or 300-microg/kg bolus, then 15-microg/kg/min infusion) in combination with abciximab or eptifibatide during PCI. The PK and PK-PD models were developed utilizing a sequential population approach in NONMEM. Population PK estimates for clearance, central volume, and peripheral volume were 22.0 L/h, 11.0 L, and 13.0 L, respectively (coefficients of variation [CVs] </= 10%). By covariate analysis, clearance increased linearly with body weight. Plasma argatroban and ACT effect were well described using a sigmoidal E(max) model. For argatroban in combination with platelet glycoprotein IIb/IIIa receptor blockade in patients undergoing PCI, population PK parameters are consistent with values reported for argatroban in healthy subjects. A predictable relationship exists between argatroban concentration and effect in this setting.
Cox
Donna S
DS
GlaxoSmithKline, Clinical Pharmacokinetics Modeling and Simulation, Clinical Pharmacology and Discovery Medicine, 709 Swedeland Road, UW 27-1013, King of Prussia, PA 19406, USA.
Kleiman
Neal S
NS
Boyle
Duane A
DA
Aluri
Jagadeesh
J
Parchman
L Gerald
LG
Holdbrook
Frederick
F
Fossler
Michael J
MJ
D000368:Aged; D000465:Algorithms; D015906:Angioplasty, Balloon, Coronary; D001120:Arginine / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D010875:Pipecolic Acids / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013449:Sulfonamides; D014914:Whole Blood Coagulation Time
D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013449:Sulfonamides; D001120:Arginine; C031942:argatroban