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

Pan, Wei-Jian, Koeck, Kathleen, Rees, William A., Sullivan, Barbara A., Evangelista, Christine M., Yen, Mark, Andrews, Jane M., Radford-Smith, Graham L., Prince, Peter J., Reynhardt, Kaz O., Doherty, David R., Patel, Sonal K., Krill, Christine D., Zhou, Kefei, Shen, Jing, Smith, Lynn E., Gow, Jason M., Lee, Jonathan, Treacy, Anthony M., Yu, Zhigang, Platt, Virginia M. and Borie, Dominic C. (2014) Clinical pharmacology of AMG 181, a gut-specific human anti-α4β7 monoclonal antibody, for treating inflammatory bowel diseases. British Journal of Clinical Pharmacology, 78 6: 1315-1333. doi:10.1111/bcp.12418


Author Pan, Wei-Jian
Koeck, Kathleen
Rees, William A.
Sullivan, Barbara A.
Evangelista, Christine M.
Yen, Mark
Andrews, Jane M.
Radford-Smith, Graham L.
Prince, Peter J.
Reynhardt, Kaz O.
Doherty, David R.
Patel, Sonal K.
Krill, Christine D.
Zhou, Kefei
Shen, Jing
Smith, Lynn E.
Gow, Jason M.
Lee, Jonathan
Treacy, Anthony M.
Yu, Zhigang
Platt, Virginia M.
Borie, Dominic C.
Title Clinical pharmacology of AMG 181, a gut-specific human anti-α4β7 monoclonal antibody, for treating inflammatory bowel diseases
Formatted title
Clinical pharmacology of AMG 181, a gut-specific human anti-α4β7 monoclonal antibody, for treating inflammatory bowel diseases
Journal name British Journal of Clinical Pharmacology   Check publisher's open access policy
ISSN 1365-2125
Publication date 2014-12
Year available 2014
Sub-type Article (original research)
DOI 10.1111/bcp.12418
Open Access Status
Volume 78
Issue 6
Start page 1315
End page 1333
Total pages 19
Place of publication Chichester, West Sussex United Kingdom
Publisher Wiley-Blackwell Publishing
Collection year 2015
Language eng
Formatted abstract
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 μg ml−1. The PD effect on α4β7 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.
Keyword α4β7 integrin
AMG 181
PK/PD
T cell trafficking
Ulcerative colitis
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Medicine Publications
 
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