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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Simultaneous Modeling of Abciximab Plasma Concentrations and ex Vivo Pharmacodynamics in Patients Undergoing Coronary Angioplasty

National Institute on Aging, Gerontology Research Center, Baltimore, Maryland (D.E.M., D.R.A.); Centocor Inc., Malvern, Pennsylvania (M.A.M.); Division of Cardiology, Baylor College of Medicine, Houston, Texas (N.S.K.); and Center for Cardiovascular Science, the Royal College of Surgeons in Ireland, Dublin, Ireland (D.J.F.)

An integrated structural pharmacokinetic/pharmacodynamic (PK/PD) model was developed for the glycoprotein IIb/IIIa antagonist abciximab administered to patients undergoing percutaneous transluminal coronary angioplasty. PK/PD data, in the form of plasma abciximab concentrations and ex vivo platelet aggregation in the presence of 20 µM adenosine diphosphate, were obtained from two previously conducted clinical studies. Study 1 consisted of patients who were given abciximab as a single intravenous injection of 0.25 mg/kg (n = 32). Patients in study 2 received an identical bolus dose, followed by a 36-h infusion at 0.125 µg/kg/min (n = 15). The PK component of the final model included drug-receptor binding, nonspecific distribution, and linear systemic clearance, whereas the PD module assumed that ex vivo dynamics were controlled by free plasma drug concentration. Mean PK/PD data from both studies were fitted simultaneously using nonlinear regression. PK profiles from both studies show rapidly decreasing plasma abciximab concentrations at early time points, but with extended terminal disposition phases. The maximum effect (E_max = 83.6%) was achieved rapidly and gradually returned to baseline values, although inhibition could be measured long after abciximab concentrations dropped below the detection limit. The final model well described the resulting PK/PD profiles and allowed for parameter estimation with relatively small coefficients of variation. Simulations were conducted to assess predicted receptor-occupancy and effects of selected parameters on PK/PD profiles. Models such as the one developed in this study demonstrate how drug binding to pharmacological targets may influence the PK of certain drugs and also provide a suitable paradigm for defining the PK/PD relationships of similar compounds.

Address correspondence to: Dr. Darrell R. Abernethy, National Institute on Aging, Gerontology Research Center, 5600 Nathan Shock Dr., Baltimore, MD 21224. E-mail: abernethyd{at}grc.nia.nih.gov