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Dose proportionality and pharmacokinetics of carvedilol sustained-release formulation: a single dose-ascending 10-sequence incomplete block study.

ABSTRACT: Carvedilol is a third-generation ?-blocker indicated for congestive heart failure and high blood pressure. The aim of this study was to investigate the dose proportionality of the carvedilol sustained-release (SR) formulation in healthy male subjects.An open-label, single dose-ascending, 10-sequence, 3-period balanced incomplete block study was performed using healthy male subjects. In varying sequences, each subject received three of five carvedilol SR formulations (8, 16, 32, 64, or 128 mg once). The treatment periods were separated by a washout period of 7 days. Serial blood samples were collected up to 48 h after dosing. The plasma concentrations of carvedilol were determined by using validated liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters including the area under the plasma concentration-time curve (AUC) from time 0 to the last measurable time (AUClast), AUC extrapolated to infinity (AUCinf), and the measured peak plasma concentration (C max) were obtained by noncompartmental analysis. Dose proportionality was evaluated if the ln-ln plots of AUClast, AUCinf, and C max versus dose were linear and the 90% confidence intervals (CIs) of the slopes were within 0.9195 and 1.0805. Tolerability was assessed by vital signs, electrocardiogram, clinical laboratory tests, and monitoring of adverse events (AEs) throughout the study.A total of 31 subjects were enrolled, and 30 completed the study. The assessment of dose proportionality meets the statistical criteria; the point estimates of slope were 1.0104 (90% CI: 0.9849-1.0359) for AUClast, 1.0003 (90% CI: 0.9748-1.0258) for AUCinf, and 0.9901 (90% CI: 0.9524-1.0277) for C max, respectively. All AEs were mild, and none of the subjects dropped out due to AEs.In this study, exposure to carvedilol was proportional over the therapeutic dose range of 8-128 mg. The carvedilol SR formulation was well tolerated.

SUBMITTER: Kim YH

PROVIDER: S-EPMC4468955 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Dose proportionality and pharmacokinetics of carvedilol sustained-release formulation: a single dose-ascending 10-sequence incomplete block study.

Kim Yo Han YH Choi Hee Youn HY Noh Yook-Hwan YH Lee Shi Hyang SH Lim Hyeong-Seok HS Kim Chin C Bae Kyun-Seop KS

Drug design, development and therapy 20150608

<h4>Background</h4>Carvedilol is a third-generation β-blocker indicated for congestive heart failure and high blood pressure. The aim of this study was to investigate the dose proportionality of the carvedilol sustained-release (SR) formulation in healthy male subjects.<h4>Methods</h4>An open-label, single dose-ascending, 10-sequence, 3-period balanced incomplete block study was performed using healthy male subjects. In varying sequences, each subject received three of five carvedilol SR formula ...[more]

PMID: 26089641

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Project description:AimsTo evaluate the safety and pharmacokinetics of naringenin in healthy adults consuming whole-orange (Citrus sinensis) extract.Methods and methodsIn a single-ascending-dose randomized crossover trial, 18 adults ingested doses of 150 mg (NAR150), 300 mg (NAR300), 600 mg (NAR600) and 900 mg (NAR900) naringenin or placebo. Each dose or placebo was followed by a wash-out period of at least 1 week. Blood safety markers were evaluated pre-dose and 24 hours post-dose. Adverse events (AEs) were recorded. Serum naringenin concentrations were measured before and over 24 hours following ingestion of placebo, NAR150 and NAR600. Four- and 24-hour serum measurements were obtained after placebo, NAR300 and NAR900 ingestion. Data were analysed using a mixed-effects linear model.ResultsThere were no relevant AEs or changes in blood safety markers following ingestion of any of the naringenin doses. The pharmacokinetic variables were: maximal concentration: 15.76 ± 7.88 μM (NAR150) and 48.45 ± 7.88 μM (NAR600); time to peak: 3.17 ± 0.74 hours (NAR150) and 2.41 ± 0.74 hours (NAR600); area under the 24-hour concentration-time curve: 67.61 ± 24.36 μM × h (NAR150) and 199.05 ± 24.36 μM × h (NAR600); and apparent oral clearance: 10.21 ± 2.34 L/h (NAR150) and 13.70 ± 2.34 L/h (NAR600). Naringenin half-life was 3.0 hours (NAR150) and 2.65 hours (NAR600). After NAR300 ingestion, serum concentrations were 10.67 ± 5.74 μM (4 hours) and 0.35 ± 0.30 μM (24 hours). After NAR900 ingestion, serum concentrations were 43.11 ± 5.26 μM (4 hours) and 0.24 ± 0.30 μM (24 hours).ConclusionsIngestion of 150 to 900 mg doses of naringenin is safe in healthy adults, and serum concentrations are proportional to the dose administered. Since naringenin (8 μM) is effective in primary human adipocytes, ingestion of 300 mg naringenin twice/d will likely elicit a physiological effect.

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Dataset Information

Dose proportionality and pharmacokinetics of carvedilol sustained-release formulation: a single dose-ascending 10-sequence incomplete block study.

Publications

Dose proportionality and pharmacokinetics of carvedilol sustained-release formulation: a single dose-ascending 10-sequence incomplete block study.

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