PMID- 26089641
OWN - NLM
STAT- MEDLINE
DCOM- 20160215
LR  - 20181203
IS  - 1177-8881 (Electronic)
IS  - 1177-8881 (Linking)
VI  - 9
DP  - 2015
TI  - Dose proportionality and pharmacokinetics of carvedilol sustained-release 
      formulation: a single dose-ascending 10-sequence incomplete block study.
PG  - 2911-8
LID - 10.2147/DDDT.S86168 [doi]
AB  - BACKGROUND: Carvedilol is a third-generation beta-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. METHODS: 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. RESULTS: 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. CONCLUSION: In this 
      study, exposure to carvedilol was proportional over the therapeutic dose range of 
      8-128 mg. The carvedilol SR formulation was well tolerated.
FAU - Kim, Yo Han
AU  - Kim YH
AD  - Department of Clinical Pharmacology and Therapeutics, College of Medicine, 
      University of Ulsan, Asan Medical Center, Seoul, Republic of Korea.
FAU - Choi, Hee Youn
AU  - Choi HY
AD  - Department of Clinical Pharmacology and Therapeutics, College of Medicine, 
      University of Ulsan, Asan Medical Center, Seoul, Republic of Korea.
FAU - Noh, Yook-Hwan
AU  - Noh YH
AD  - Department of Clinical Pharmacology and Therapeutics, College of Medicine, 
      University of Ulsan, Asan Medical Center, Seoul, Republic of Korea.
FAU - Lee, Shi Hyang
AU  - Lee SH
AD  - Department of Clinical Pharmacology and Therapeutics, College of Medicine, 
      University of Ulsan, Asan Medical Center, Seoul, Republic of Korea.
FAU - Lim, Hyeong-Seok
AU  - Lim HS
AD  - Department of Clinical Pharmacology and Therapeutics, College of Medicine, 
      University of Ulsan, Asan Medical Center, Seoul, Republic of Korea.
FAU - Kim, Chin
AU  - Kim C
AD  - Chong Kun Dang Clinical Research and Clinical Epidemiology and Medical 
      Information, CKD Pharmaceuticals, Seoul, Republic of Korea.
FAU - Bae, Kyun-Seop
AU  - Bae KS
AD  - Department of Clinical Pharmacology and Therapeutics, College of Medicine, 
      University of Ulsan, Asan Medical Center, Seoul, Republic of Korea.
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20150608
PL  - New Zealand
TA  - Drug Des Devel Ther
JT  - Drug design, development and therapy
JID - 101475745
RN  - 0 (Adrenergic beta-Antagonists)
RN  - 0 (Carbazoles)
RN  - 0 (Delayed-Action Preparations)
RN  - 0 (Propanolamines)
RN  - 0K47UL67F2 (Carvedilol)
SB  - IM
MH  - Adrenergic beta-Antagonists/administration & dosage/adverse 
      effects/*pharmacokinetics
MH  - Adult
MH  - Area Under Curve
MH  - Carbazoles/administration & dosage/adverse effects/*pharmacokinetics
MH  - Carvedilol
MH  - Chromatography, High Pressure Liquid/methods
MH  - Delayed-Action Preparations
MH  - Dose-Response Relationship, Drug
MH  - Humans
MH  - Male
MH  - Propanolamines/administration & dosage/adverse effects/*pharmacokinetics
MH  - Tandem Mass Spectrometry
MH  - Young Adult
PMC - PMC4468955
OTO - NOTNLM
OT  - carvedilol
OT  - dose linearity
OT  - healthy subjects
OT  - sustained release
EDAT- 2015/06/20 06:00
MHDA- 2016/02/16 06:00
PMCR- 2015/06/08
CRDT- 2015/06/20 06:00
PHST- 2015/06/20 06:00 [entrez]
PHST- 2015/06/20 06:00 [pubmed]
PHST- 2016/02/16 06:00 [medline]
PHST- 2015/06/08 00:00 [pmc-release]
AID - dddt-9-2911 [pii]
AID - 10.2147/DDDT.S86168 [doi]
PST - epublish
SO  - Drug Des Devel Ther. 2015 Jun 8;9:2911-8. doi: 10.2147/DDDT.S86168. eCollection 
      2015.