PHARMACOKINETICS AND PHARMACODYNAMICS OF INTRAVENOUS OPC-18790 IN HUMANS - A NOVEL NONGLYCOSIDIC INOTROPIC AGENT

OPC-18790, a nonglycosidic intropic agent, is now under clinical devel opment for treatment of congestive heart failure. Two separate studies (one placebo-controlled) were conducted to evaluate its pharmacokinet ics and pharmacodynamics after intravenous administration to a total o f 36 healthy male subjects. The drug was administered both rapidly as a.05-,.1-,.2-, or .4-mg/kg intravenous dose, and as a 1-hour infusion of .5, 1.0, 2.5, 5.0, 10.0, or 15.0 mu g/kg/minute. Echocardiograms (E CHO) were evaluated before and immediately and 4 hours after the rapid administrations. Blood pressure (BP), heart rate (HR), and QTc in the electrocardiogram also were monitored in the rapid administration stu dy. OPC-18790 was generally well tolerated by all subjects. Maximum pe ak plasma concentration and area under the curve increased linearly wi th dose in both studies. The t1/2, total body clearance of drug from p lasma (CL), and the dose fraction excreted unchanged in the urine (fe) were comparable and dose-independent at the doses tested in both stud ies. The overall mean values of t1/2 alpha, t1/2 beta, CL, and fe were .08 +/- .01 hours, 3.64 +/- .22 hours, .46 +/- .01 L/kg, and 43.5 +/- 1.0%, respectively. Echocardiograms showed that, immediately after ra pid administration of up to .4 mg/kg, OPC-18790 increased left cardiac function dose-proportionally (P <.05 to .01): the ejection fraction b y 21.1% and fractional shortening by 26.5% compared with the predose v alues, blood pressure, heart rate, and QTc did not differ between subj ects given OPC-18790 and these receiving placebo. Intravenous OPC-1879 0 at the dose ranges used is considered to be safe and tolerable and e xerts positive inotropic effects in a dose-proportional manner. This d rug is potentially useful in the treatment of severe congestive heart failure.