Shin Dongseong, Lee SeungHwan, Yi Sojeong, Yoon Seo Hyun, Cho Joo-Youn, Bahng Mi Young, Jang In-Jin, Yu Kyung-Sang
Clinical Trials Center, Gachon University Gil Medical Center, Incheon.
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital.
Drug Des Devel Ther. 2017 Mar 10;11:713-723. doi: 10.2147/DDDT.S126861. eCollection 2017.
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.
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.
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-normalized and AUC of 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.
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.
DA - 8031是一种正在研发的用于治疗早泄的选择性5-羟色胺再摄取抑制剂。这是一项首次在人体进行的研究，旨在评估健康男性受试者单次口服给药后，DA - 8031及其代谢产物（M1、M2、M4和M5）在血浆和尿液中的药代动力学及耐受性。
进行了一项剂量分组随机、双盲、安慰剂对照、单剂量递增研究。受试者分别接受安慰剂或5、10、20、40、60、80或120 mg的单剂量DA - 8031。分析血浆和尿液中的DA - 8031及其四种代谢产物以进行药代动力学评估。评估细胞色素P450（CYP）酶的基因多态性对DA - 8031药代动力学的影响。
单次给药后，血浆中DA - 8031在中位时间2 - 3小时达到最大浓度，消除半衰期为17.9 - 28.7小时。平均肾清除率为3.7 - 5.6 L/h。在20 - 80 mg剂量范围内观察到剂量比例药代动力学。在代谢产物中，M4的血浆浓度最高，其次是M5和M1。CYP2D6中间代谢型受试者的DA - 8031剂量标准化Cmax和AUC显著高于CYP2D6广泛代谢型受试者，且代谢比更小。最常见的不良事件为恶心、头晕和头痛，未报告严重不良事件。
总之，在20 - 80 mg范围内，DA - 8031的全身暴露量与剂量成比例增加。CYP2D6基因多态性对DA - 8031的全身暴露有影响。80 mg及以下单剂量的DA - 8031耐受性良好。
