title: Pharmacokinetics and pharmacodynamics of intravenous OPC-18790 in humans: a novel nonglycosidic inotropic agent.
abstract: OPC-18790, a nonglycosidic intropic agent, is now under clinical development for treatment of congestive heart failure. Two separate studies (one placebo-controlled) were conducted to evaluate its pharmacokinetics and pharmacodynamics after intravenous administration to a total of 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 micrograms/kg/minute. Echocardiograms (ECHO) 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 study. OPC-18790 was generally well tolerated by all subjects. Maximum peak plasma concentration and area under the curve increased linearly with dose in both studies. The t1/2, total body clearance of drug from plasma (CL), and the dose fraction excreted unchanged in the urine (fe) were comparable and dose-independent at the doses tested in both studies. 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 rapid administration of up to .4 mg/kg, OPC-18790 increased left cardiac function dose-proportionally (P < .05 to .01): the ejection fraction by 21.1% and fractional shortening by 26.5% compared with the predose values, blood pressure, heart rate, and QTc did not differ between subjects given OPC-18790 and these receiving placebo.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Internal Medicine, Daisan Hospital, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Ohnishi
authors.forename: T
authors.initials: T
authors.lastname: Toyoki
authors.forename: T
authors.initials: T
authors.lastname: Ohno
authors.forename: Y
authors.initials: Y
authors.lastname: Takeshige
authors.forename: T
authors.initials: T
authors.lastname: Fujita
authors.forename: K
authors.initials: K
authors.lastname: Kodama
authors.forename: M
authors.initials: M
authors.lastname: Mishima
authors.forename: A
authors.initials: A
authors.lastname: Hirayama
authors.forename: M
authors.initials: M
authors.lastname: Kitani
authors.forename: G
authors.initials: G
authors.lastname: Miyamoto
mesh_terms: D000328:Adult; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D004452:Echocardiography; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D002316:Cardiotonic Agents; D015363:Quinolones; C077543:toborinone