title: Pharmacokinetics, safety and tolerability of DA-6034, an anti-inflammatory agent, after single and multiple oral administrations in healthy volunteers.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea.
authors.forename: Jieon
authors.initials: J
authors.lastname: Lee
authors.forename: Kwang-Hee
authors.initials: KH
authors.lastname: Shin
authors.forename: Jung-Ryul
authors.initials: JR
authors.lastname: Kim
authors.forename: Kyoung Soo
authors.initials: KS
authors.lastname: Lim
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Jae-Yong
authors.initials: JY
authors.lastname: Chung
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005419:Flavonoids / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D005419:Flavonoids; C121889:recoflavone