Abstract
A phase I study of E-1020, a newly synthesized selective phosphodiesterase inhibitor that possesses both positive inotropic and vasodilatory properties, was carried out in healthy Japanese male volunteers.
E-1020 was administered by intravenous infusion to evaluate its safety, and to establish its pharmacokinetic and pharmacodynamic profiles, at doses of 1. 25 μg/kg to 50 μg/kg with 5-min infusion (Step 1 to Step 7) and at doses of 61. 25 μg/kg to 163. 75 μg/kg with a combination of 15-min loading dose and following 165-min maintenance dose (Step 8 to Step 10).
E-1020 was generally well tolerated by all subjects at each dose level, except for episodes of mild hyperemia in the eyes, a warm feeling in the face and/or the earlobes, and palpitation. These symptoms disappeared within a few hours after dosing, and seemed to be attributable to the pharmacological effects of the drug. Significant increments of heart rate were observed at the dose of 50 μg/kg (Step 7) and 61. 25 μg/kg to 163. 75 μg/kg (Step 8 to Step 10). However, no clinically significant changes in blood pressure, electrocardiograms, or clinical laboratory test values were noted.
A significant increase in the mean values of the fractional shortening as assessed by echocardiography was observed after administration of the higher doses of E-1020.
The plasma pharmacokinetics of E-1020 could be best described by an open linear two-compartment kinetic model. The half life in the β-phase was about 1 hr in all steps. The urinary excretion was about 80% of the dose, and mostly unchanged form.
We conclude that the drug posesses a good tolerance and no clinically significant adverse effect as demonstrated in the present dose range of E-1020. Thus it is suitable for further clinical studies.
