Clinical pharmacology of AMG 181, a gut-specific human anti-α4β7 monoclonal antibody, for treating inflammatory bowel diseases

Wei-Jian Pan, Kathleen Kock, Williams Rees, Barbara Sullivan, Christine Evangelista, Mark Yen, Jane Andrews, Graham Radford-Smith, Peter Prince, Kaz Reynhardt, David Doherty, Sonal Patel, Christine Krill, Kefei Zhou, Jing Shen, Lynn Smith, Jason Gow, Jonathan Lee, Anthony Treacy, Zhigang YuVirginia Platt, Dominic Borie

    Research output: Contribution to journalArticlepeer-review

    28 Citations (Scopus)


    AIMS 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), α4β7 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 μgml-1. The PD effect on α4β7 RO showed an EC50 of 0.01 μgml-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.

    Original languageEnglish
    Pages (from-to)1315-1333
    Number of pages19
    JournalBritish Journal of Clinical Pharmacology
    Issue number6
    Publication statusPublished - Dec 2014


    • AMG 181
    • PK/PD
    • T cell trafficking
    • Ulcerative colitis
    • α4β7 integrin


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