Pharmacokinetics and tolerability of DA-8031, a novel selective serotonin reuptake inhibitor for premature ejaculation in healthy male subjects.
OBJECTIVE
DA-8031 is a selective serotonin reuptake inhibitor under development for the treatment of premature ejaculation. This is the first-in-human study aimed at evaluating the pharmacokinetics and tolerability of DA-8031 and its metabolites (M1, M2, M4, and M5) in the plasma and urine after administration of a single oral dose in healthy male subjects.


METHODS
A dose block-randomized, double-blind, placebo-controlled, single ascending dose study was conducted. Subjects received either placebo or a single dose of DA-8031 at 5, 10, 20, 40, 60, 80, or 120 mg. DA-8031 and its four metabolites were analyzed in the plasma and urine for pharmacokinetic evaluation. The effect of genetic polymorphisms of cytochrome-P450 (CYP) enzymes on the pharmacokinetics of DA-8031 was evaluated.


RESULTS
After a single dose, plasma DA-8031 reached the maximum concentration at a median of 2-3 h and was eliminated with terminal elimination half-life of 17.9-28.7 h. The mean renal clearance was 3.7-5.6 L/h. Dose-proportional pharmacokinetics was observed over the dose range of 20-80 mg. Among the metabolites, M4 had the greatest plasma concentration, followed by M5 and M1. Subjects with CYP2D6 intermediate metabolizer had significantly greater dose-normalizedCmaxand AUC0-tof DA-8031 as well as smaller metabolic ratios than those subjects with CYP2D6 extensive metabolizer. The most common adverse events were nausea, dizziness, and headache, and no serious adverse events were reported.


CONCLUSIONS
In conclusion, the systemic exposure of DA-8031 was increased proportionally to the dose within 20-80 mg. Genetic polymorphisms of CYP2D6 had an effect on the systemic exposure of DA-8031. DA-8031 was well tolerated after single doses of 80 mg or less.
Clinical Trials Center, Gachon University Gil Medical Center, Incheon.
Dongseong
D
Shin
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital.
SeungHwan
S
Lee
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital.
Sojeong
S
Yi
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital.
Seo Hyun
SH
Yoon
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital.
Joo-Youn
JY
Cho
Department of Product Development, Dong-A ST, Seoul, Korea.
Mi Young
MY
Bahng
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital.
In-Jin
IJ
Jang
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital.
Kyung-Sang
KS
Yu
D000328:Adult; D001572:Benzofurans / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D015394:Molecular Structure; D061686:Premature Ejaculation / Q000188:drug therapy*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*
D001572:Benzofurans; D017367:Selective Serotonin Reuptake Inhibitors; C559089:DA 8031
DA-8031; first-in-human; pharmacokinetics; premature ejaculation; selective serotonin reuptake inhibitor