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.

Population pharmacokinetics of S(-)-carvedilol in healthy volunteers after administration of the immediate-release (IR) and the new controlled-release (CR) dosage forms of the racemate.

Carvedilol is a beta(1)-, beta(2)-, and alpha(1)-adrenoreceptor blocker indicated for treatment of hypertension and mild-to-severe congestive heart failure. The objective of this study was to develop and evaluate a single population model that describes S(-)-carvedilol pharmacokinetics from both the immediate-release (IR) and the new controlled-release dosage forms of the racemate. Carvedilol IR data (1270 measurements) were obtained from 2 open-label studies (50 mg/25 mg Q12 hours for 2 doses). Carvedilol CR data (2058 measurements) were obtained from an open-label, nonrandomized, dose-rising (10, 20, 40, and 80 mg), 4-period balanced crossover study. All data were simultaneously analyzed using NONMEM V. Leverage analysis and internal evaluations were conducted for the final model. A 2-compartment model with first-order absorption and elimination provided the best fit. The model included different absorption rates (KAs) for the CR and IR morning (IR(AM)) and evening (IR(PM)) doses; incorporating change-points at certain times. Estimates of KAs indicated that the absorption was slower at equivalent times and extended for CR relative to IR carvedilol. Oral clearance of S(-)-carvedilol was 149 L/h. The IR(PM) and the CR doses had bioavailability (F(rel)) of 0.80 and 0.76, respectively, relative to the IR(AM) dose. The inter-subject variability in KAs was lower for the CR dosage form than the original IR dosage form. Estimation of interoccasion variability on KAs and F(rel) for the CR dosage form improved the fit. The model performed well in simulation and leverage analysis indicated its robustness. The model will be a useful tool for future simulation studies.

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.

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 /=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.

Investigation of the interaction between argatroban and acetaminophen, lidocaine, or digoxin.

The potential pharmacokinetic interactions between argatroban and acetaminophen, lidocaine, or digoxin were examined. Three randomized crossover studies were conducted. In the first study, 11 subjects completed three sessions (with a five-day washout period between sessions), receiving two 500-mg acetaminophen caplets at 0, 6, 12, 18, and 24 hours; i.v. argatroban 1.5 micrograms/kg/min from hours 12 to 30; or a combination of both. In the second study, 12 subjects completed three sessions (with a five-day washout period between sessions), receiving lidocaine hydrochloride injection 2 mg/kg/hr for 16 hours (after receiving a loading dose of 1.5 mg/kg over 10 minutes), i.v. argatroban 1.5 micrograms/kg/min for 16 hours, or a combination of both. In the third study, 12 subjects completed two sessions (with a seven-day washout period between sessions), receiving oral digoxin 0.375 mg/day for 15 days and either i.v. placebo or argatroban 2 micrograms/kg/min on days 11 through 15. Primary pharmacokinetic values in each study included area under the drug concentration versus time curve and steady-state concentrations of argatroban and the concomitantly administered drug. Lack of a pharmacokinetic interaction (individually defined for each study) was demonstrated in each study. Argatroban, regardless of acetaminophen or lidocaine administration, prolonged activated partial thromboplastin time values approximately 1.6-1.8 times the baseline values. No deaths, unexpected adverse events, or clinically significant changes in safety laboratory values occurred. No pharmacokinetic interaction was detected between argatroban and acetaminophen, lidocaine, or digoxin. Argatroban is well tolerated during coadministration with these drugs. In practice, argatroban coadministered with these frequently prescribed drugs should require no dosage adjustments.