Ethanol does not alter the pharmacokinetic profile of the controlled-release formulation of carvedilol.

The concomitant ingestion of alcohol may alter the release of a drug from a modified-release dosage form, posing a potential risk to patients. In a randomized, open-label, 4-period cross-over study, the pharmacokinetic profiles of R(+) and S(-) carvedilol were compared after a single oral dose of carvedilol controlled-release formulation (administered following a standard meal) was given alone or concomitantly with ethanol. Thirty-nine healthy subjects participated in this study. Following coadministration of carvedilol controlled-release 40 mg with ethanol (approximately 38 g), ethanol ingestion 2 hours before or 2 hours after carvedilol controlled-release administration, area under the curve for the R(+) and S(-) carvedilol enantiomers was similar compared with carvedilol controlled-release given alone. Carvedilol exposure was not affected by the concomitant administration of ethanol and carvedilol controlled-release. Maximum plasma concentrations for the R(+) and S(-) carvedilol enantiomers were similar except when ethanol was ingested 2 hours after carvedilol controlled-release administration, where there was a modest decrease in maximum plasma concentration for R(+) and S(-) carvedilol (16% and 17%, respectively). Carvedilol controlled-release given alone or concomitantly with ethanol ingestion was generally well tolerated, and no serious or severe adverse events were reported. Ethanol did not alter the pharmacokinetic profile of carvedilol controlled-release.

Pharmacokinetic properties of a new controlled-release formulation of carvedilol.

This review summarizes the pharmacokinetics (PK) of carvedilol after administration of a new once-daily controlled-release (CR) formulation. The plasma concentration-time profiles for both R(+)- and S(-)-carvedilol indicate that carvedilol CR will provide coverage over a 24-hour period similar to the current immediate-release (IR) twice-daily formulation. Exposures for both enantiomers, based on area under the curve (AUC), maximum plasma concentrations (C(max)), and trough concentrations, are equivalent for carvedilol CR compared with carvedilol IR. C(max) and AUC of the enantiomers of carvedilol increase in an approximate dose-proportional manner after administration of carvedilol CR over the dose range of 10-80 mg, indicating that the formulation provides consistent PK performance across the dose strengths proposed for marketing. The intrasubject and intersubject variability of carvedilol CR was comparable to carvedilol IR. For carvedilol CR, mean AUC and C(max) were increased <20% after a high-fat meal compared with a standard meal. The CR and IR formulations of carvedilol exhibited equivalent steady-state PK characteristics in the target hypertension and heart failure populations. The availability of once-daily dosing is expected to improve treatment adherence and thereby enhance the effectiveness of carvedilol in routine clinical use.

Development of a pharmacokinetic/pharmacodynamic model for carvedilol to predict beta1-blockade in patients with congestive heart failure.

To determine whether the controlled-release (CR) formulation of carvedilol given once daily provides 24-hour beta1-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 beta-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 beta-blocking coverage for the new CR formulation of carvedilol given once daily.

Pharmacokinetic and pharmacodynamic comparison of controlled-release carvedilol and immediate-release carvedilol at steady state in patients with hypertension.

Carvedilol is indicated for the treatment of essential hypertension and mild-to-severe chronic heart failure, as well as the reduction of cardiovascular mortality in clinically stable post-myocardial infarction patients with left ventricular dysfunction. Carvedilol is a racemic mixture of R(+) and S(-) enantiomers that combines beta(1)-, beta(2)-, and alpha(1)-adrenoceptor blockade. For all indications, the immediate-release (IR) formulation of carvedilol is taken twice daily. A controlled-release (CR) formulation of carvedilol that allows once-daily dosing has recently been developed. In this double-blind, parallel-group, crossover study, 122 patients with essential hypertension were randomly allocated to receive low and high doses of carvedilol or placebo. Patients received either a constant low dose (CR 20 mg once daily or IR 6.25 mg twice daily) or were titrated to a high dose (CR 80 mg once daily or IR 25 mg twice daily) before being crossed over to an equivalent dose of the alternative formulation. The pharmacokinetic (PK) and pharmacodynamic (PD) profiles were compared between patients receiving carvedilol CR and carvedilol IR. The PK profiles for R(+)- and S(-)-carvedilol for the 2 formulations were equivalent (based on area under the curve, maximum plasma concentration [C(max)], and trough drug concentration). Consistent with an extended-release formulation, carvedilol CR delayed C(max) by 3.5 hours compared with carvedilol IR. For both carvedilol CR and IR, the attenuation of exercise-induced heart rate in patients with hypertension was maintained over the entire 24-hour period, and the 2 formulations demonstrated equivalent beta(1)-blocking effects at trough (end of the dosing interval [PD(min)]), suggesting that the rate of absorption does not interfere with the PD effect. In this first direct comparison of carvedilol CR and IR in subjects with hypertension, fewer adverse events were reported while subjects were receiving carvedilol CR (59.1% overall) compared with carvedilol IR (77.5% overall). This was true regardless of dose received. Headache was the most commonly reported adverse event for subjects receiving either formulation of carvedilol and placebo. Importantly, dizziness and headache were reported less often when subjects received carvedilol CR. This is the first study to show that both formulations had comparable beta(1)-adrenergic blockade in patients with essential hypertension under steady-state conditions. Notably, carvedilol CR provides consistent beta(1)-adrenergic blockade over 24 hours with a once-daily dose.