Changes in Cardiac Function After a Single Intravenous Administration of CKD-712 in Healthy Male Volunteers.

Abstract

CKD-712, a candidate treatment for septic shock, acts by increasing cardiac output. This study investigated changes in the pharmacodynamics, pharmacokinetics, and tolerability of CKD-712 after a single intravenous administration. A dose-block-randomized, double-blind, placebo-controlled, single-dose escalation study was conducted in 44 healthy subjects receiving 20, 40, 80, 160, 240, or 320μg/kg CKD-712 or placebo. Pharmacodynamics were evaluated using computerized impedance cardiography, vital signs, platelet aggregation, and bleeding time. Serial blood and urine samples for pharmacokinetic analysis were collected up to 12 and 24h, respectively, after the initiation of intravenous drug infusion. Tolerability assessments were performed throughout the study. The area under the effect-time curve of the cardiac index (AUECCI) and systolic blood pressure (AUECSBP) changed significantly with the 160 and 320µg/kg doses of CKD-712 compared with placebo. Furthermore, the AUECCI and AUECSBP tended to increase as the systemic exposure of CKD-712 increased from 20 to 240µg/kg. The frequency of drug-related adverse events (AEs), including cardiovascular symptoms, was higher with the 320µg/kg dose. The pharmacological effects and on-target AEs of CKD-712 increased relative to the dose increments. The results of this study suggest that potentially therapeutic doses of CKD-712 could range from 160 to 240μg/kg.