The pharmacokinetics of pimobendan enantiomers after oral and intravenous administration of racemate pimobendan formulations in healthy dogs

Abstract

Pimobendan is a benzimidazole-pyridazinone derivative, marketed as a racemic mixture for the management of canine heart failure. Pharmacokinetics of the enantiomers of pimobendan and its oral bioavailability have not been described in dogs. The aim of this study was to describe pharmacokinetics of three formulations of pimobendan in healthy dogs: the licensed capsule product, and novel liquid and intravenous formulations. A three-period, nested randomized two-treatment crossover design was used. Pimobendan was administered p.o. at 0.25 and i.v. at 0.125 mg/kg. Blood and plasma samples were analysed by liquid chromatography-mass spectrometry. Noncompartmental modelling was used to describe the pharmacokinetics. Parameters were compared between formulations using a general linear model. Bioequivalence of the oral formulations was tested using CI90 for AUC(0-∞) and Cmax . Bioavailability of pimobendan after oral dosing was 70%. Liquid and capsule formulations were bioequivalent only for AUC. The positive enantiomer of pimobendan (PE) had a larger volume of distribution than the negative enantiomer (NE) (281 ± 48 vs. 215 ± 68 mL/kg; P = 0.003) and a shorter half-life (21.7 vs. 29.9 min; P = 0.004). The NE was distributed more quickly than the PE into blood cells. Enantiomers of pimobendan have differing absorption, distribution and elimination. The pharmacokinetics of pimobendan in healthy dogs was described.

Pharmacokinetics of Pimobendan and Its Metabolite O-Desmethyl-Pimobendan Following Rectal Administration to Healthy Dogs

“…However, the therapeutic efficacy of the plasma concentrations reported in our study is difficult to interpret, partly because the plasma concentrations associated with the presumed efficacy of PIM and OMDP are not clearly defined in dogs. The authors noticed a disparity among the pharmacokinetic profiles of pimobendan reported by others (1,6,21). The key pharmacokinetic parameters of PIM and ODMP from different studies are summarized in Table 2.…”

“…The key pharmacokinetic parameters of PIM and ODMP from different studies are summarized in Table 2 . Pimobendan capsule 0.25 mg/kg resulted in a C max of 38.1 ± 18.3 ng/ml ( 1 ). In two other studies, both using pimobendan suspensions (but different products), 0.27 mg/kg of a pimobendan suspension produced C max of 18.6 ng/ml (6.1–25.3), yet 0.3 mg/kg resulted in a C max of 7.3 ± 2.7 ng/ml ( 6 , 21 ).…”

“…Pimobendan, a benzimidazole-pyridazinone derivative, is known as an inodilator that possesses the unique combination of a positive inotrope and a vasodilator (1). It acts as a positive inotrope by sensitizing the affinity of calcium for binding to troponin C on cardiac myocytes and inhibiting phosphodiesterase 3 (PDE3).…”

“…The inhibition of PDE3 also results in both arterial dilation and venodilation. As a result, pimobendan improves the cardiac output without increasing the myocardial oxygen consumption (1)(2)(3). This unique combination of properties makes pimobendan desirable in the treatment of congestive heart failure (CHF) secondary to myxomatous mitral valve disease or dilated cardiomyopathy in dogs (2)(3)(4)(5).…”

“…While the oral bioavailability of the commercial tablet is 70% (1,2,6), oral administration is not a viable route in an emergency situation. Many dogs presenting with advanced stage of CHF are in severe respiratory distress on presentation.…”