To determine whether the controlled-release (CR) formulation of carvedilol given once daily provides 24-hour β₁-receptor blockade similar to the currently marketed immediate-release (IR) formulation given twice daily, changes in exercise-induced heart rate after bicycle ergometry were measured. The pharmacokinetic (PK)/pharmacodynamic (PD) relation between S(−)-carvedilol concentration—the enantiomer with β-blocking activity—and change in exercise-induced heart rate was defined in healthy subjects and was best described using a direct effect inhibitory E_max model (with E_max being the maximum effect). The population estimates for E_max and concentration at 50% of the maximum effect (EC₅₀) were 19.2 beats per minute (an approximately 13% maximum decrease in exercise-induced heart rate) and 7.7 ng/mL, respectively. The PK/PD model was used to predict PD effects in patients with mild-to-severe heart failure and in patients after myocardial infarction with left ventricular dysfunction who had received both the IR and CR formulations of carvedilol. In these patients, carvedilol CR had equivalent predicted overall PD (area under the effect curve) and trough (PD_min) effects compared with carvedilol IR, indicating 24-hour β-blocking coverage for the new CR formulation of carvedilol given once daily.