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Changes in Cardiac Function After a Single Intravenous Administration of CKD-712 in Healthy Male Volunteers
Sang-In Park1, JaeWoo Kim2, Kyung-Sang Yu1
1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
Insights
CKD-712, a potential septic shock treatment, increased cardiac output in a dose-dependent manner. Therapeutic doses may range from 160 to 240 μg/kg, with higher doses showing increased adverse events.
Area of Science:
- Pharmacology
- Clinical Pharmacology
- Septic Shock Therapeutics
Background:
- CKD-712 is a novel therapeutic agent designed to improve cardiac output.
- Septic shock management requires treatments that enhance cardiovascular function.
Purpose of the Study:
- To evaluate the pharmacodynamics, pharmacokinetics, and tolerability of CKD-712.
- To determine the dose-response relationship of CKD-712 in healthy subjects.
Main Methods:
- A single-dose escalation study involving 44 healthy participants.
- Doses of CKD-712 ranged from 20 to 320 μg/kg, with placebo controls.
- Pharmacodynamic assessments included cardiac output, blood pressure, and platelet aggregation.
Main Results:
- Significant increases in cardiac index and systolic blood pressure were observed at 160 and 320 μg/kg doses.
- Dose-dependent increases in pharmacological effects and systemic exposure were noted.
- Higher incidence of cardiovascular adverse events occurred at the 320 μg/kg dose.
Conclusions:
- CKD-712 demonstrates dose-related pharmacological effects and on-target adverse events.
- The potential therapeutic dose range for CKD-712 is suggested to be 160-240 μg/kg.
Background And Objectives:
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.
Methods:
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 320 μg/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 24 h, respectively, after the initiation of intravenous drug infusion. Tolerability assessments were performed throughout the study.
Results:
The area under the effect-time curve of the cardiac index (AUECCI) and systolic blood pressure (AUECSBP) changed significantly with the 160 and 320 µg/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 240 µg/kg. The frequency of drug-related adverse events (AEs), including cardiovascular symptoms, was higher with the 320 µg/kg dose.
Conclusion:
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 240 μg/kg.
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