title: Evaluation of the pharmacokinetics, food effect, pharmacodynamics, and tolerability of DA-1229, a dipeptidyl peptidase IV inhibitor, in healthy volunteers: first-in-human study.
abstract: BACKGROUND
  Inhibitors of dipeptidyl peptidase (DPP) IV are a class of oral hypoglycemic agents that increase glucagon-like peptide-1 (GLP-1) levels by inhibiting its degradation.
  
  
  OBJECTIVE
  This study evaluated the pharmacokinetics, pharmacodynamics, and tolerability of DA-1229, which is a newly developed DPP IV inhibitor. This study was planned as part of a product development project at the request of the Korean regulatory agency.
  
  
  METHODS
  A 7 parallel arm dose-escalation study was conducted in healthy Korean male volunteers. A single oral dose of DA-1229 or placebo was given to 10 subjects (8 active + 2 placebo) in each dose group of 1.25, 2.5, 5, 10, 20, 40, or 60 mg. To assess the effects of food, the subjects in the 10-mg dose group received a single dose of DA-1229 10 mg after a high-fat meal, crossing over from the administration of DA-1229 under a fasting state, after a 7-day washout period. Serial blood samples were collected up to 120 hours after drug administration for pharmacokinetic analysis and the assessment of DPP IV activity, and blood samples were collected up to 2 hours after each meal until the next morning of drug administration to evaluate active GLP-1, glucose, and insulin levels.
  
  
  RESULTS
  Seventy-two subjects, aged 20 to 39 years and weighing 52.1 to 79.8 kg, participated in this study. Twenty-one adverse events were reported; all were mild, and all subjects recovered spontaneously. DA-1229 reached a peak at 3.0 to 5.5 hours after a single oral dose and the concentrations declined, with a terminal t(½) from 32.5 to 39.8 hours. The %CV of C(max) and AUC(0-last) ranged from 11.1% to 54.6%. Dose-proportional pharmacokinetics were confirmed within the dose range by using a linear regression analysis, and the 95% CIs of the slope of the log-transformed C(max) and AUC(0-last) included 1.0. The pharmacokinetics of DA-1229 were unchanged by food. The degree of DPP IV inhibition was dependent on the dose, and groups receiving ≥10 mg exhibited >80% DPP IV inhibition for >24 hours. The %CV of the time of the last quantifiable concentration ranged from 4.6% to 15.2%. C(max) of active GLP-1 was achieved at 30 minutes after meal intake. The active GLP-1 levels were enhanced in groups receiving ≥5 mg. There were no changes in the glucose and insulin levels after DA-1229 administration.
  
  
  CONCLUSIONS
  DA-1229 was well tolerated within the dose range of 1.25 to 60 mg. DA-1229 pharmacokinetics suggested dose proportionality, and dose-dependent DPP IV inhibition was exhibited. ClinicalTrials.gov identifier: NCT00961025.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, National University College of Medicine and Hospital, Jongno-gu, Seoul, Korea.
authors.forename: Tae-Eun
authors.initials: TE
authors.lastname: Kim
authors.forename: Kyoung Soo
authors.initials: KS
authors.lastname: Lim
authors.forename: Min Kyu
authors.initials: MK
authors.lastname: Park
authors.forename: Seo-Hyun
authors.initials: SH
authors.lastname: Yoon
authors.forename: Joo-Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: Sang-Goo
authors.initials: SG
authors.lastname: Shin
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001786:Blood Glucose / Q000187:drug effects; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D018565:Food-Drug Interactions; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D016014:Linear Models; D008297:Male; D010879:Piperazines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D056910:Republic of Korea; D055815:Young Adult
chemical_list: C557982:4-(3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(tert-butoxymethyl)piperazin-2-one; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D010879:Piperazines; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4