Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of enalkiren (Abbott-64662, a renin inhibitor). II: A dose-ranging study in patients with congestive heart failure.

This study describes the relationship between the measured effects (the acute effects on systemic hemodynamics and cardiac function) and plasma drug levels using a combined pharmacokinetic-pharmacodynamic model after i.v. infusion dosing of enalkiren (A-64662) in patients with congestive heart failure. Ascending doses from 0.003 to 1.0 mg/kg were evaluated. Timed blood samples were obtained to measure enalkiren levels in plasma. The plasma level-effect plots showed little or no hysteresis. A sigmoid Emax model was used to develop the relationship between the predicted plasma enalkiren levels and hemodynamic effects. Although hemodynamic effects were observed for most patients, random noise in the dynamics or modest net effects compared to baseline fluctuations precluded simultaneous modeling of the pharmacokinetics and pharmacodynamics for a few patients. While the sensitivity toward enalkiren's effects varied substantially among this group of patients, the studywide estimates of the EC50 for the blood pressure measures averaged about 3,500 ng/ml. The mean EC50 for systolic blood pressure (SBP, 2,744 ng/ml) was lower than those of diastolic blood pressure (DBP, 3,438 ng/ml) and mean arterial pressure (MAP, 3,371 ng/ml), suggesting that the SBP might be a more sensitive measure than the other two.