This study describes the relationship between the measured effects (angiotensin I and renal plasma flow) and plasma drug levels using a combined pharmacokinetic-pharmacodynamic model after 90 min iv infusion of enalkiren in 15 healthy, salt-depleted subjects. Doses from 0.002 to 0.512 mg/kg were evaluated. One hour prior to enalkiren dosing, para-aminohippuric acid infusion was started for each subject and continued until 3 hr after the start of enalkiren infusion. Timed blood samples were obtained to measure enalkiren, para-aminohippuric acid, and angiotensin I levels in plasma. Enalkiren-induced effect changes lagged in time behind the plasma enalkiren level changes, showing a counterclockwise hysteresis loop. To relate the temporal relationship of effect changes accurately to plasma drug levels, a pharmacokinetic model was combined with a pharmacokinetic model that incorporated a hypothetical effect compartment. The magnitude of the time lag was quantified by the half-time of equilibration between concentrations in the hypothetical effect compartment and the plasma enalkiren levels (t1/2keo). The t1/2keo for angiotensin I (0.002 hr) is significantly shorter than that of renal plasma flow (0.267 hr), indicating that enalkiren equilibrates more rapidly with the angiotensin I-related effect compartment than the renal plasma flow-related effect compartment. Moreover, the model allows for estimation of the effect site concentration that causes one-half of the maximal predicted effect (EC50), which is a measure of an individual's sensitivity to enalkiren. The EC50 of angiotensin I (81.1 ng/ml) is substantially lower than that of renal plasma flow (4414 ng/ml), indicating that angiotensin I may be a more sensitive measure of enalkiren effects than renal plasma flow.