title: Clinical pharmacology of AMG 181, a gut-specific human anti-α4β7 monoclonal antibody, for treating inflammatory bowel diseases.
abstract: OBJECTIVE
  AMG 181 pharmacokinetics/pharmacodynamics (PK/PD), safety, tolerability and effects after single subcutaneous (s.c.) or intravenous (i.v.) administration were evaluated in a randomized, double-blind, placebo-controlled study.
  
  
  METHODS
  Healthy male subjects (n= 68) received a single dose of AMG 181 or placebo at 0.7, 2.1, 7, 21, 70 mg s.c. (or i.v.), 210 mg s.c. (or i.v.), 420 mg i.v. or placebo. Four ulcerative colitis (UC) subjects (n= 4, male : female 2:2) received 210 mg AMG 181 or placebo s.c. (3:1). AMG 181 concentration, anti-AMG 181-antibody (ADA), α4 β7 receptor occupancy (RO), target cell counts, serum C-reactive protein, fecal biomarkers and Mayo score were measured. Subjects were followed 3-9 months after dose.
  
  
  RESULTS
  Following s.c. dosing, AMG 181 was absorbed with a median tmax ranging between 2-10 days and a bioavailability between 82% and 99%. Cmax and AUC increased dose-proportionally and approximately dose-proportionally, respectively, within the 70-210 mg s.c. and 70-420 mg i.v. ranges. The linear β-phase t1/2 was 31 (range 20-48) days. Target-mediated disposition occurred at serum AMG 181 concentrations of less than 1 μg ml(-1) . The PD effect on α4 β7 RO showed an EC50 of 0.01 μg ml(-1) . Lymphocytes, eosinophils, CD4+ T cells and subset counts were unchanged. AMG 181-treated UC subjects were in remission with mucosal healing at weeks 6, 12 and/or 28. The placebo-treated UC subject experienced colitis flare at week 6. No ADA or AMG 181 treatment-related serious adverse events were observed.
  
  
  CONCLUSIONS
  AMG 181 has PK/PD, safety, and effect profiles suitable for further testing in subjects with inflammatory bowel diseases.
authors.affiliation: Amgen Inc., Seattle, Washington, USA.
authors.forename: Wei-Jian
authors.initials: WJ
authors.lastname: Pan
authors.forename: Kathleen
authors.initials: K
authors.lastname: Köck
authors.forename: William A
authors.initials: WA
authors.lastname: Rees
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Sullivan
authors.forename: Christine M
authors.initials: CM
authors.lastname: Evangelista
authors.forename: Mark
authors.initials: M
authors.lastname: Yen
authors.forename: Jane M
authors.initials: JM
authors.lastname: Andrews
authors.forename: Graham L
authors.initials: GL
authors.lastname: Radford-Smith
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Prince
authors.forename: Kaz O
authors.initials: KO
authors.lastname: Reynhardt
authors.forename: David R
authors.initials: DR
authors.lastname: Doherty
authors.forename: Sonal K
authors.initials: SK
authors.lastname: Patel
authors.forename: Christine D
authors.initials: CD
authors.lastname: Krill
authors.forename: Kefei
authors.initials: K
authors.lastname: Zhou
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
authors.forename: Lynn E
authors.initials: LE
authors.lastname: Smith
authors.forename: Jason M
authors.initials: JM
authors.lastname: Gow
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lee
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Treacy
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Yu
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Platt
authors.forename: Dominic C
authors.initials: DC
authors.lastname: Borie
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D008297:Male
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C000591337:abrilumab
keywords: AMG 181; PK/PD; T cell trafficking; ulcerative colitis; α4β7 integrin