Pharmacokinetic profile of controlled-release carvedilol in patients with left ventricular dysfunction associated with chronic heart failure or after myocardial infarction.

We compared the pharmacokinetic (PK) profiles of repeated dosing with the currently available immediate-release (IR) carvedilol (given twice daily) and a newly developed controlled-release (CR) formulation (given once daily) in patients with left ventricular dysfunction (LVD). We enrolled 188 patients with stable mild, moderate, or severe heart failure as well as survivors of a recent acute myocardial infarction (MI) with asymptomatic LVD (left ventricular ejection fraction </=0.40) in a crossover study. PK variables were initially assessed after patients had received carvedilol IR 3.125, 6.25, 12.5, or 25 mg twice daily for >/=2 weeks. Patients were then switched to the corresponding dose of carvedilol CR (10, 20, 40, or 80 mg once daily), and PK variables were reassessed after an additional 2 weeks. The primary measures included trough plasma concentration (C(tau)), maximum plasma concentration (C(max)), and area under the concentration-time curve (AUC([0-t])) for both enantiomers of carvedilol of each formulation of the drug. The AUC((0-t)) and the trough and maximum carvedilol concentrations for both the R(+) and S(-) enantiomers were similar when carvedilol IR was compared with carvedilol CR as follows: 3.125 mg twice daily versus 10 mg once daily, 6.25 mg twice daily versus 20 mg once daily, 12.5 mg twice daily versus 40 mg once daily, and 25 mg twice daily versus 80 mg once daily, respectively. Based on a pooled analysis, the AUC((0-t)), C(max), and C(tau) for both R(+) and S(-) were equivalent for the CR and IR formulations, with point estimates and 90% confidence intervals within the bioequivalence limits of 80%-125%. The fluctuation index (the CR-IR ratio for [C(max) - C(min)]/C(ss) where C(min) is the minimum observed concentration over the dosing interval and C(ss) is the concentration at steady state) for both R(+)- and S(-)-carvedilol was approximately 1, indicating that the peak-to-trough fluctuation in plasma concentration for carvedilol after use of carvedilol CR once daily was similar to that for carvedilol IR given twice daily. The median time to maximum observed plasma concentration (t(max)) was approximately 3 hours longer for both enantiomers after administration of carvedilol CR as compared with carvedilol IR. These data demonstrate that the new carvedilol CR formulation given once daily is equivalent to the currently available carvedilol IR formulation given twice daily in patients with heart failure and asymptomatic post-MI LVD.