Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea.
Clin Drug Investig. 2014 Jan;34(1):37-42. doi: 10.1007/s40261-013-0147-0.
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract. DA-6034 has been shown to be effective in an IBD model and has demonstrated a good toxicological profile in preclinical studies. This study evaluated the tolerability, safety and pharmacokinetics of DA-6034 in healthy volunteers.
A double-blind, randomized, placebo-controlled, ascending-dose study was conducted in 67 healthy volunteers. In the single-ascending-dose study, 10, 20, 50, 100 or 200 mg of DA-6034 was administered orally to 40 subjects; in the multiple-ascending-dose study, 40, 100 or 200 mg/day of DA-6034 was administered orally to 27 subjects for 7 days. Serial blood and urine samples were taken for pharmacokinetic analysis. Plasma drug concentrations were determined by high-performance liquid chromatography. Safety and tolerability were assessed throughout the study.
DA-6034 had minimal absorption, and the pharmacokinetic parameters were highly variable among subjects. For both the single- and multiple-dose administrations, the coefficients of variation of the area under the plasma concentration-time curve to the last observation (AUClast) and the area under the plasma concentration-time curve over the dosing interval at steady state (AUCss,τ) ranged from 16.0 to 125.0 %. At doses of up to 200 mg of DA-6034, the mean maximum plasma concentration (C max) was <3 ng/mL, and the urine recovery ratio was 0.3 % of the dose, indicating a lack of absorption. Twenty-two mild adverse events were reported in 14 subjects. There were no serious adverse events and no significant changes in the safety assessment.
DA-6034 was well tolerated and minimally absorbed in healthy volunteers. The non-systemic, local exposure of the gastrointestinal tract to DA-6034 may be advantageous for IBD treatment.
炎症性肠病（IBD）是一种胃肠道的慢性炎症性疾病。DA-6034 在 IBD 模型中已被证明是有效的，并且在临床前研究中表现出良好的毒理学特征。本研究评估了 DA-6034 在健康志愿者中的耐受性、安全性和药代动力学。
一项双盲、随机、安慰剂对照、递增剂量的研究在 67 名健康志愿者中进行。在单次递增剂量研究中，40 名受试者口服给予 10、20、50、100 或 200mg 的 DA-6034；在多次递增剂量研究中，27 名受试者每日口服给予 40、100 或 200mg 的 DA-6034，连续 7 天。连续采集血样和尿样进行药代动力学分析。通过高效液相色谱法测定血浆药物浓度。在整个研究过程中评估安全性和耐受性。
DA-6034 几乎没有吸收，药代动力学参数在受试者之间高度可变。无论是单次还是多次给药，最后一次观测时的血浆浓度-时间曲线下面积（AUClast）和稳态下的血浆浓度-时间曲线下面积（AUCss,τ）的变异系数（CV）范围为 16.0%至 125.0%。在高达 200mg 的 DA-6034 剂量下，平均最大血浆浓度（C max）<3ng/mL，尿液回收率为剂量的 0.3%，表明吸收不足。14 名受试者中有 22 名报告了 22 例轻度不良事件。无严重不良事件，安全性评估无显著变化。
DA-6034 在健康志愿者中耐受良好，几乎没有吸收。胃肠道局部暴露于 DA-6034 的非系统性可能有利于 IBD 的治疗。
