SIMULTANEOUS MODELING OF THE PHARMACOKINETIC AND PHARMACODYNAMIC PROPERTIES OF ENALKIREN (ABBOTT-64662, A RENIN INHIBITOR) .2. A DOSE-RANGING STUDY IN PATIENTS WITH CONGESTIVE-HEART-FAILURE

This study describes the relationship between the measured effects (th e acute effects on systemic hemodynamics and cardiac function) and pla sma drug levels using a combined pharmacokinetic-pharmacodynamic model after i.v. infusion dosing of enalkiren (A-64662) in patients with co ngestive heart failure. Ascending doses from 0.003 to 1.0 mg/kg were e valuated. Timed blood samples were obtained to measure enalkiren level s in plasma. The plasma level-effect plots showed little or no hystere sis. A sigmoid E(max) model was used to develop the relationship betwe en the predicted plasma enalkiren levels and hemodynamic effects. Alth ough hemodynamic effects were observed for most patients, random noise in the dynamics or modest net effects compared to baseline fluctuatio ns precluded simultaneous modeling of the pharmacokinetics and pharmac odynamics for a few patients. While the sensitivity toward enalkiren's effects varied substantially among this group of patients, the studyw ide estimates of the EC50 for the blood pressure measures averaged abo ut 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 th e SBP might be a more sensitive measure than the other two.