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Pharmacokinetics and Pharmacodynamics of Argatroban in Combination With a Platelet Glycoprotein IIB/IIIA Receptor Antagonist in Patients Undergoing Percutaneous Coronary Intervention

From GlaxoSmithKline Pharmaceuticals, Clinical Pharmacokinetics/Modeling and Simulation (Dr. Cox, Dr. Boyle, Dr. Fossler, Mr. Aluri), Clinical Pharmacology and Discovery Medicine, King of Prussia, Pennsylvania; Clinical Development and Medical Affairs (Dr. Parchman), Cardiovascular/Genito-urinary Therapeutic Area, King of Prussia, Pennsylvania; Biomedical Data Sciences (Dr. Holdbrook), Biostatistics and Programming, King of Prussia, Pennsylvania; and Baylor College of Medicine, Houston, Texas (Dr. Kleiman). GlaxoSmithKline Pharmaceuticals (Philadelphia, PA) and Encysive Pharmaceuticals (Houston, TX) provided study support.

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-µg/kg bolus, then 15-µg/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.

Key Words: Argatroban • percutaneous coronary intervention • platelet GPIIb/IIIa receptor antagonists • activated clotting time • pharmacokinetics • pharmacodynamics

Address for reprints: Donna S. Cox, PhD, GlaxoSmithKline, Clinical Pharmacokinetics Modeling and Simulation, Clinical Pharmacology and Discovery Medicine, 709 Swedeland Road, UW 27-1013, King of Prussia, PA 19406.

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