Pharmacodynamic properties
Pimobendan, a benzimadazole-pyridazinone derivative has a positively inotropic action and possesses pronounced vasodilator properties.
The positive inotropic effect of pimobendan is mediated by two action mechanisms: increase in calcium sensitivity of cardiac myofilaments and inhibition of phosphodiesterase III. Thus the positive inotropism is triggered neither by an action similar to that of the cardiac glycosides nor sympathomimetically.
The vasodilator effect arises from inhibition of phosphodiesterase III.
When used in cases of symptomatic valvular insufficiency in conjunction with furosemide the product has been shown to improve the quality of life and extend life expectancy in treated dogs.
When used in a limited number of cases of symptomatic dilated cardiomyopathy in conjunction with furosemide, enalapril and digoxin, the product has been shown to improve the quality of life and to extend life expectancy in treated dogs.
In a randomized and placebo controlled study in 363 dogs with preclinical myxomatous mitral valve disease, all dogs met the following inclusion criteria: age ≥ 6 years, bodyweight ≥ 4.1 and ≤ 15 kg, characteristic systolic heart murmur of moderate to high intensity (≥grade 3/6) with maximal intensity over the mitral area; echocardiographic evidence of advanced myxomatous mitral valve disease (MMVD) defined as characteristic valvular lesions of the mitral valve apparatus, echocardiographic evidence of left atrial and left ventricular dilatation and radiographic evidence of cardiomegaly (vertebral heart sum (VHS) > 10.5. The median time to onset of clinical signs of heart failure or cardiac death/euthanasia was extended in these dogs by approximately 15 months. Additionally, there was a reduction in the heart size of dogs treated with pimobendan in the preclinical stage of myxomatous mitral valve disease. Furthermore, overall survival time was prolonged by approximately 170 days in all dogs receiving pimobendan independent of their cause of death (cardiac death/ euthanasia and non-cardiac death/euthanasia). Cardiac related death or euthanasia occurred in 15 dogs in the pimobendan group and 12 dogs in the placebo group prior to the onset of CHF. Dogs in the pimobendan group spent a longer time in the study (347.4 patient years) than those in the placebo group (267.7 patient years) resulting in a lower rate of occurrence.
In a randomized and placebo controlled study including Doberman Pinschers with preclinical dilated cardiomyopathy (asymptomatic with an increase in left ventricular end-systolic and end-diastolic diameter following echocardiographic diagnosis), the time to onset of congestive heart failure or sudden death was extended and survival time was prolonged among dogs administered pimobendan.
Additionally, there was a reduction in the heart size of dogs treated with pimobendan in the preclinical stage of dilated cardiomyopathy. Efficacy evaluation is based on data from 19 (of 39) and 25 (of 37) dogs that reached the primary efficacy endpoint in the pimobendan and the placebo group, respectively.
Pharmacokinetic particulars
Absorption: After oral administration of this veterinary medicinal product the absolute bioavailability of its active substance is 60 - 63%. Since simultaneous or previous food intake reduces the bioavailability, pimobendan should be administered about 1 hour before feeding.
Distribution: The volume of distribution is 2.6 l/kg, indicating that pimobendan is distributed readily into the tissues. The mean plasma protein binding is 93%.
Metabolism: The compound is demethylated by oxidation to the major active metabolite (UD-CG212). Further metabolic steps are phase II conjugates of UD-CG212, such as glucuronides and sulphates.
Elimination:The plasma elimination half-life of pimobendan is 0.4 ± 0.1 hours, which corresponds to the high clearance of 90 ± 19 ml/min/kg and the short mean residence of 0.5 ± 0.1 hours.
The most significant active metabolite is eliminated with a plasma elimination half-life of 2.0 ± 0.3 hours. Almost the entire dose is eliminated in the faeces.