Document Detail

Population pharmacokinetics of R- and S-carvedilol in Japanese patients with chronic heart failure.
MedLine Citation:
PMID:  20686235     Owner:  NLM     Status:  MEDLINE    
Carvedilol is a beta-adrenoceptor antagonist used for treating chronic heart failure (CHF). Two clinical studies were conducted to evaluate the population pharmacokinetics and pharmacodynamics of R- and S-carvedilol, and associated covariates, in patients with CHF. Fifty-eight patients (male=45, female=13) with New York Heart Association class I-IV CHF were enrolled in two clinical studies. R- and S-carvedilol concentrations were measured using HPLC at steady-state after oral administration of carvedilol at 1.25-20 mg o.d. or b.i.d. The data from both studies were used to estimate the population pharmacokinetic parameters and covariates using the nonlinear mixed effects model program. For 40 patients evaluated in one clinical study, the cytochrome P450 (CYP)2D6 *1, *10, and *5 genotypes were determined using allele-specific primer PCR, and individual patients' oral clearance (CL/F) of both enantiomers were estimated by the empirical Bayes method. A one-compartment model with a first-order absorption rate was established, in which body weight and alpha(1)-acid glycoprotein were significant covariates. Individual CL/F values for carvedilol were significantly lower in Japanese CHF patients with the CYP2D6 *1/*5, *5/*10 and *10/*10 genotypes. Estimation of the population pharmacokinetic parameters and their covariates for each enantiomer in Japanese patients with CHF showed that the CL/F values for R- and S-carvedilol were dependent on body weight, alpha(1)-acid glycoprotein, and CYP2D6 genotype. Prediction of exposure to free plasma carvedilol is important for dosage adjustment of beta-blocker therapy in patients with CHF.
Masako Saito; Junichi Kawana; Tetsuro Ohno; Kazuhiko Hanada; Masahiro Kaneko; Kiyoshi Mihara; Mari Shiomi; Masatoshi Nagayama; Tetsuya Sumiyoshi; Hiroyasu Ogata
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Publication Detail:
Type:  Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biological & pharmaceutical bulletin     Volume:  33     ISSN:  1347-5215     ISO Abbreviation:  Biol. Pharm. Bull.     Publication Date:  2010  
Date Detail:
Created Date:  2010-08-05     Completed Date:  2010-12-14     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  9311984     Medline TA:  Biol Pharm Bull     Country:  Japan    
Other Details:
Languages:  eng     Pagination:  1378-84     Citation Subset:  IM    
Department of Biopharmaceutics, Meiji Pharmaceutical University, Kiyose, Tokyo 204-8588, Japan.
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MeSH Terms
Administration, Oral
Adrenergic beta-Antagonists / adverse effects,  blood,  pharmacokinetics*,  therapeutic use
Aged, 80 and over
Bayes Theorem
Carbazoles / adverse effects,  blood,  pharmacokinetics*,  therapeutic use
Chronic Disease
Cytochrome P-450 CYP2D6 / genetics
Gene Frequency
Genetics, Population
Heart Failure / blood,  drug therapy*,  enzymology
Metabolic Clearance Rate
Middle Aged
Propanolamines / adverse effects,  blood,  pharmacokinetics*,  therapeutic use
Grant Support
//Wellcome Trust
Reg. No./Substance:
0/Adrenergic beta-Antagonists; 0/Carbazoles; 0/Propanolamines; 0K47UL67F2/carvedilol; EC P-450 CYP2D6

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