Pharmacokinetics, Tolerability and Pharmacogenetics of DA-8031 After Multiple Ascending Doses in Healthy Male Subjects

• Published in: Drug design, development and therapy Vol. 15; pp. 2375 - 2384
• Main Authors: Hwang, Sejung, Lee, Dae Young, Cho, Joo-Youn, Chung, Jae-Yong, Jang, In-Jin, Yu, Kyung-Sang, Lee, SeungHwan
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01-01-2021; Taylor & Francis Ltd; Dove; Dove Medical Press
• Subjects: Administration, Oral; Adult; Adverse events; Analysis; Antidepressants; Benzofurans - administration & dosage; Benzofurans - blood; Benzofurans - pharmacokinetics; clinical pharmacology; Clinical trials; CYP2D6 protein; Cytochrome; Cytochrome P-450; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P450; Dosage; Dose-Response Relationship, Drug; Double-Blind Method; Drug dosages; Drug Tolerance; Ejaculation; EKG; Electrocardiogram; Electrocardiography; Enzymes; Exposure; Gene polymorphism; Generalized linear models; Genetic analysis; Genetic polymorphisms; Healthy Volunteers; Humans; Male; Males; Metabolism; Metabolites; Middle Aged; Oral administration; Original Research; Pharmacogenetics; pharmacogenomics; Pharmacokinetics; Pharmacology; phase 1 study; Placebos; Polymorphism, Genetic - drug effects; Polymorphism, Genetic - genetics; Safety; selective serotonin reuptake inhibitors; Serotonin; Serotonin uptake inhibitors; Serotonin Uptake Inhibitors - administration & dosage; Serotonin Uptake Inhibitors - blood; Serotonin Uptake Inhibitors - pharmacokinetics; Sexual disorders; Statistical analysis; Variance analysis; Young Adult; Canada; South Korea; United States > US; clinical pharmacology; pharmacogenomics; phase 1 study; selective serotonin reuptake inhibitors
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S309763

DA-8031 is a novel selective serotonin reuptake inhibitor for the treatment of premature ejaculation. This study investigated the pharmacokinetics, safety and tolerability of multiple oral doses of DA-8031. In addition, a genetic analysis was explored to evaluate the effect of genetic polymorphisms on the pharmacokinetics of DA-8031.
A dose block-randomized, double-blind, placebo-controlled study was conducted in 3 dose groups with 20, 30 and 40 mg of DA-8031. Healthy male subjects were randomized to DA-8031 or placebo at a 4:1 ratio in each dose group of 10 subjects by oral administration once daily for 7 consecutive days. Serial blood and urine samples were collected for the pharmacokinetic evaluation, and the pharmacokinetic-related genes were analyzed by DMET
plus. A safety evaluation was conducted including adverse events (AEs) monitoring and 12-lead electrocardiogram (ECG).
The plasma DA-8031 concentration reached the maximum concentration (C
) in 2.2 to 3.0 h and was eliminated with a mean half-life of 25.5 to 26.7 h at steady state. The accumulation index of DA-8031 ranged 2.3 to 2.8. The systemic exposure of DA-8031 of the CYP2D6 intermediate metabolizer (IM) was significantly higher compared to the CYP2D6 poor metabolizer (PM). There were no clinically significant QTc interval changes, and all the adverse events were mild.
After multiple oral doses of DA-8031 20, 30, and 40 mg in this study, the systemic exposure of DA-8031 increased in a more than dose-proportional manner with the increasing doses, and DA-8031 was generally well tolerated. In addition, the genetic polymorphisms of CYP2D6 have an impact on the pharmacokinetics of DA-8031.