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Research ArticleArticle

Cardiovascular Effect and Simultaneous Pharmacokinetic and Pharmacodynamic Modeling of Pimobendan in Healthy Normal Subjects

Kai-Min Chu, Oliver Yoa-Pu Hu and Shyh-Ming Shieh
Drug Metabolism and Disposition June 1999, 27 (6) 701-709;
Kai-Min Chu
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Oliver Yoa-Pu Hu
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Shyh-Ming Shieh
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Abstract

Pimobendan is a new inotropic agent with vasodilator properties. We have reported the pharmacokinetics of enantiomers of pimobendan in healthy humans. The present report focuses on the pharmacodynamic effect of pimobendan and a simultaneous pharmacokinetic-pharmacodynamic modeling. Eight normal healthy volunteers were studied with oral administration of 7.5 mg and i.v. administration of 5 mg of racemic pimobendan. Concentrations of enantiomers of pimobendan were determined by high performance liquid chromatography. Cardiovascular effects of pimobendan were evaluated by echocardiography. Oral pimobendan significantly reduced 29.0% and 16.5% of the left ventricle end-systolic dimension (LVESD) and end-diastolic dimension, respectively. The mean velocity of circumferential fiber shortening, ejection fraction, and fractional shortening significantly increased 105.9%, 29.8%, and 46% from their baseline values, respectively. The cardiovascular effects of i.v. pimobendan were similar but to a lesser extent. Plots of effect versus plasma concentration (Cp) showed counterclockwise hysteresis loops. A hypothetical effect compartment was established and incorporated into a sigmoid Emax model to describe the time courses of Cps of pimobendan and effects on LVESD. The maximal changes (Emax) in LVESD would be 2.60 ± 0.51 cm and 2.30 ± 0.13 cm as estimated from plasma data of (+)- and (−)-pimobendan, respectively. The estimated effect-site concentrations corresponding with 50% of the maximal effect (Ce50) were 6.54 ± 1.35 and 6.64 ± 1.35 ng/ml for (+)- and (−)-pimobendan, respectively. A simultaneous pharmacokinetic-pharmacodynamic model could be established to suppress the hysteresis loop and to predict the pharmacological effect based on Cp.

Footnotes

  • Send reprint requests to: Dr. Oliver Yoa-Pu Hu, Professor and Director, Pharmaceutical Research Institute, National Defense Medical Center, P.O. Box 90048–508, Taipei, Taiwan, Republic of China. E-mail: hyp{at}ndmc1.ndmtsgh.edu.tw

  • This work was partially supported by the Institute of Biomedical Sciences, Academia Sinica, Republic of China.

  • Abbreviations used are::
    pimo
    pimobendan
    AOPV
    aortic flow peak velocity
    BP
    blood pressure
    Ce
    effect-site concentration
    Ce50
    effect-site concentration corresponding with 50% of the maximal effect
    CI
    cardiac index
    CO
    cardiac output
    Cp
    plasma concentration
    CV
    coefficient of variation
    dP/dt
    rate of change in pressure over time
    EF
    ejection fraction
    Emax
    maximal effect
    E0
    calculated baseline effect
    E0(obs)
    observed baseline effect
    Eest
    estimated effect
    Eobs
    observed effect
    HR
    heart rate
    ke0
    elimination rate constant of the hypothetical effect compartment
    LA
    left atrium
    LVEDD
    left ventricle end-diastolic dimension
    LVESD
    left ventricle end-systolic dimension
    LVET
    left ventricular ejection time
    MVcf
    mean velocity of circumferential fiber shortening
    MVPV
    mitral valve-flow peak velocity
    PD
    pharmacodynamic
    PEP
    pre-ejection period
    PK
    pharmacokinetic
    SV
    stroke volume
    SVI
    stroke volume index
    ΔTmax
    lag-time between Tmax(e) and Tmax
    Tmax
    time to reach peak concentration
    Tmax(e)
    time to reach peak effect
    • Received September 11, 1998.
    • Accepted February 10, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (6)
Drug Metabolism and Disposition
Vol. 27, Issue 6
1 Jun 1999
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Research ArticleArticle

Cardiovascular Effect and Simultaneous Pharmacokinetic and Pharmacodynamic Modeling of Pimobendan in Healthy Normal Subjects

Kai-Min Chu, Oliver Yoa-Pu Hu and Shyh-Ming Shieh
Drug Metabolism and Disposition June 1, 1999, 27 (6) 701-709;

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Research ArticleArticle

Cardiovascular Effect and Simultaneous Pharmacokinetic and Pharmacodynamic Modeling of Pimobendan in Healthy Normal Subjects

Kai-Min Chu, Oliver Yoa-Pu Hu and Shyh-Ming Shieh
Drug Metabolism and Disposition June 1, 1999, 27 (6) 701-709;
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