Controlled-Release Carvedilol in Heart Failure and Post-MI LVD: Pharmacokinetics, Pharmacodynamics and Safety

Abstract

Objective: We compared pharmacokinetic (PK) and predicted pharmacodynamic (PD) profiles of immediate-release carvedilol (IR) and a novel, once-daily controlled-release (CR) carvedilol formulation in patients (pts) with heart failure (HF) or post-myocardial infarction (MI) left ventricular dysfunction (LVD). Research Design and Methods: In this open, nonrandomized, multicenter, crossover study we included pts with stable mild to severe HF and asymptomatic survivors of a recent MI with LV ejection fraction ≤ 40%. Pts received their standard carvedilol IR dose for 2 weeks followed by 24-hr PK assessment; they were switched to an equivalent dose of carvedilol CR (10, 20, 40 or 80 mg once a day). Carvedilol CR and IR were compared for observed steady-state PK (area under the concentration-time curve [AUC], trough plasma concentration [Cmin], and maximum plasma concentration [Cmax]). Predicted steady-state PD (area under the effect curve [AUEC], maximum effect [PDmax], and PD at trough [PDmin]) was assessed for the two formulations based on a PK/PD model developed in healthy volunteers for changes in exercise induced heart rate. Results: Of 187 pts entered (28% mild, 29% moderate, 27% severe HF; 16% asymptomatic post-MI LVD), 93% completed the study. Mean exposure was 28.3 days (range 1 to 51). Doses used were 20% carvedilol CR 10 mg, 29% 20 mg, 27% 40 mg, and 24% 80 mg. Consistent with its extended-release properties, median tmax was 3 h longer with carvedilol CR vs. IR and the Fluctuation index (CR:IR ratio for [Cmax-Cmin]/concentration at steady state [Css]) was approximately 1. Based on analysis of data pooled across all pt and dose groups, carvedilol CR and IR had equivalent observed PK and predicted PD effects. Both formulations were well tolerated; when pts switched to carvedilol CR there were 20 (11%) events during the first week of therapy with 2 reports of dizziness. Conclusions: Pharmacokinetic parameters for the CR and IR carvedilol formulations were equivalent in pts with mild to severe HF or asymptomatic post-MI LVD. Predicted PD effects (AUEC, PDmin, and PDmax) were also equivalent. When administered as either formulation, carvedilol was generally safe and well-tolerated in this study. These data support the use of carvedilol CR in HF and post MI-LVD patients.