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


CONCLUSIONS
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.
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
Sang-In
SI
Park
Clinical Trials Center, Chungnam National University Hospital, Daejeon, Republic of Korea.
JaeWoo
J
Kim
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
Kyung-Sang
KS
Yu
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
In-Jin
IJ
Jang
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea. leejh413@snu.ac.kr.
SeungHwan
S
Lee
D000328:Adult; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage* / Q000494:pharmacology; D055815:Young Adult
D044005:Tetrahydroisoquinolines; C090309:YS 49