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

Abstract

Carvedilol is a b 1 -, b 2 -, and a 1 -adrenoreceptor blocker indicated for treatment of hypertension and mild-tosevere 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 controlledrelease 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 fi t. 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 fi t. The model performed well in simulation and leverage analysis indicated its robustness. The model will be a useful tool for future simulation studies.

Race differences: modeling the pharmacodynamics of rosuvastatin in Western and Asian hypercholesterolemia patients

“…Consequently, the final model, a simple E max model with a fixed E 0 (-0.812%), was successfully used to describe rosuvastatin pharmacodynamics. Moreover, the robustness of the final model was evaluated by the nonparametric bootstrap and the datasplitting methods [51,52] , which indicated that selected combinations of data yielded results very similar to those obtained using the original full data set. The predictive performance of the final model was confirmed by the visual predictive check using Monte Carlo simulations, which showed that the mean values of LDL-C reduction (%) from the one-dose trials were mostly distributed within the 5th-to 95th-percentile boundaries of the predictive dose-response profiles for both Westerners and Asians.…”

Models for evaluating the pharmacokinetics and pharmacodynamics for β-blockers

“…In order to compare intersubject variability, PK parameters of S-carvedilol were estimated by means of a two-compartment model with first-order absorption and elimination. The main finding of the study was the detection of a lower intersubject variability in the rate of S-carvedilol oral absorption for the CR formulation with regards to the IR dosage form [38].…”

“…In this context, a single population PK model has been developed to describe S-carvedilol PK from the immediate release (IR) and the CR dosage forms of the racemate [38]. In order to compare intersubject variability, PK parameters of S-carvedilol were estimated by means of a two-compartment model with first-order absorption and elimination.…”

“…Lower intersubject variability in the rate of S-carvedilol oral absorption for the CR formulation with regards to the IR dosage form [38] Metoprolol Middle-aged and elderly patients One-compartment model CYP2D6*10 allele associated with increase in bioavailability CYP2C19 genotype, gender and heart failure showed no significant effects on the PKs of metoprolol [39,40] PK: Pharmacokinetic.…”

Controlled-release carvedilol in the management of systemic hypertension and myocardial dysfunction

“…This difference contributes, in part, to slightly higher milligram dosage strengths of carvedilol CR than the "equivalent" carvedilol IR doses . A model of carvedilol pharmacokinetics that takes into consideration both the IR and CR formulations has been developed and performed robustly in leverage analyses (Othman et al 2007). Similar to carvedilol IR, the bioavailability and pharmacokinetics of carvedilol CR are infl uenced by food, and both formulations are recommended to be taken with food .…”