Cardiovascular effect and simultaneous pharmacokinetic and pharmacodynamicmodeling of pimobendan in healthy normal subjects

Pimobendan is a new inotropic agent with vasodilator properties. We have re ported the pharmacokinetics of enantiomers of pimobendan in healthy humans. The present report focuses an the pharmacodynamic effect of pimobendan and a simultaneous pharmacokinetic-pharmaco dynamic modeling. Eight normal hea lthy volunteers were studied with oral administration of 7.5 mg and i.v. ad ministration of 5 mg of racemic pimobendan. Concentrations of enantiomers o f pimobendan were determined by high performance liquid chromatography, Car diovascular 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 m ean velocity of circumferential fiber shortening, ejection fraction, and fr actional shortening significantly increased 105.9%, 29.8%, and 46% from the ir;baseline values, respectively. The cardiovascular effects of i.v. pimobe ndan were similar but to a lesser extent. Plots of effect versus plasma con centration (C-p) showed counterclockwise hysteresis loops. A hypothetical e ffect compartment was established and incorporated into a sigmoid E-max mod el to describe the time courses of C(p)s of pimobendan and effects on LVESD . The maximal changes (E-max) in LVESD would be 2.60 +/- 0.51 cm and 2.30 /- 0.13 cm as estimated from plasma data of (+)- and (-)-pimobendan, respec tively. The estimated effect-site concentrations corresponding with 50% of the maximal effect (C-e50) were 6.54 +/- 1.35 and 6.64 + 1.35 ng/ml for (+) - and (-)-pimobendan, respectively. A simultaneous pharmacokinetic-pharmaco dynamic model could be established to suppress the hysteresis loop and to p redict the pharmacological effect based on C-p.