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
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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
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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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