Clinical pharmacology of intravenous enoximone: Pharmacodynamics and pharmacokinetics in patients with heart failure

Twenty-one patients with heart failure (New York Heart Association [NYHA] class II to IV) received a 24-hour infusion of enoximone followed by a 12-hour washout period. Patients were randomly assigned to one of four treatment groups. Groups I to III received an 0.5 mg/kg bolus, followed by a maintenance infusion of 2.5, 5.0, or 10.0 μg/kg/min. Group IV patients received a maintenance infusion of 5.0 μg/kg/min without a loading dose. Serial assessment of hemodynamics, plasma levels of enoximone and enoximone sulfoxide, and ventricular ectopy were performed. Enoximone produced a clinically significant increase in cardiac index, and a decrease in mean pulmonary artery wedge pressure and systemic vascular resistance in all groups. Enoximone mildly increased heart rate, and had a minimal effect on mean arterial pressure. There was no statistically significant change in ventricular ectopy during the infusion. Significant hemodynamic improvement was noted at even the lowest infusion rate, and did not increase in linear fashion at higher infusion rates. In patients who did not receive an initial loading bolus of 0.5 mg/kg, the increase in cardiac index was delayed by approximately 1 hour. Plasma concentrations of both enoximone and its major metabolite continued to rise throughout the 24-hour infusion in group III (10.0 μg/kg/min), rather than reaching steady state as predicted by the terminal exponential half-lives of these compounds. This is suggestive of nonlinear pharmacokinetics and indicates a potential for excessive accumulation of enoximone and its metabolite during prolonged infusion. These findings may have important implications in gulding the intravenous administration of enoximone. Intravenous doses of enoximone above 5.0 μg/kg/min may not provide very much additional hemodynamic benefit compared with lower doses and yet may result in significant accumulation of enoximone and its metabolites, leading to an increased potential for toxicity. An initial intravenous bolus of enoximone should be administered prior to continous infusion of enoximone in cases where immediate hemodynamic benefit is desirable.