Pharmacokinetics and pharmacodynamics of the antiarrhythmic compound MD750819 in dogs with experimentally induced arrhythmias

Abstract

Pharmacokinetics and pharmacodynamics were studied in three dogs with interventricular coronary artery ligatures (ligature of Harris) and in three control animals. Weighted nonlinear analysis was used to fit equations describing two and three compartment open models to the experimental data, obtained after intravenous injection (5 mg/kg) of the drug. The three compartment model gave a reduction in the weighted sum of squared residuals and an improvement in the randomness of scatter of the experimental points about the theoretical curve. The postdistribution elimination half-life was longer, the area under the plasma elimination curve larger, and the total body plasma clearance and apparent volume of distribution was reduced in the animals with arrhythmias. The pharmacological response was assessed by recording the ECG and calculating the percentage of normal sinus rhythm/min. A combined pharmacokinetic-pharmacodynamic model was used to analyze data from individual animals. k_e0, a measure of the lag time of pharmacological response behind changes in plasma concentration, and C_e (50), a measure of the sensitivity of the cardiac site of action of the drug, were determined.