Population Pharmacokinetics of R- and S-Carvedilol in Japanese Patients with Chronic Heart Failure

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  • Saito Masako
    Department of Biopharmaceutics, Meiji Pharmaceutical University
  • Kawana Junichi
    Department of Pharmacy, Sakakibara Heart Institute, Japan Research Promotion Society for Cardiovascular Diseases
  • Ohno Tetsuro
    Department of Pharmacy, Sakakibara Heart Institute, Japan Research Promotion Society for Cardiovascular Diseases
  • Hanada Kazuhiko
    Department of Biopharmaceutics, Meiji Pharmaceutical University
  • Kaneko Masahiro
    Department of Biopharmaceutics, Meiji Pharmaceutical University
  • Mihara Kiyoshi
    Department of Biopharmaceutics, Meiji Pharmaceutical University
  • Shiomi Mari
    Department of Biopharmaceutics, Meiji Pharmaceutical University
  • Nagayama Masatoshi
    Department of Cardiology, Sakakibara Heart Institute, Japan Research Promotion Society for Cardiovascular Diseases
  • Sumiyoshi Tetsuya
    Department of Cardiology, Sakakibara Heart Institute, Japan Research Promotion Society for Cardiovascular Diseases
  • Ogata Hiroyasu
    Department of Biopharmaceutics, Meiji Pharmaceutical University

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Carvedilol is a β-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 α1-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, α1-acid glycoprotein, and CYP2D6 genotype. Prediction of exposure to free plasma carvedilol is important for dosage adjustment of β-blocker therapy in patients with CHF.

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