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Clinical pharmacology of AMG 181, a gut‐specific human anti‐α 4 β 7 monoclonal antibody, for treating inflammatory bowel diseases
Author(s) -
Pan WeiJian,
Köck Kathleen,
Rees William A.,
Sullivan Barbara A.,
Evangelista Christine M.,
Yen Mark,
Andrews Jane M.,
RadfordSmith 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.
Publication year - 2014
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12418
Subject(s) - pharmacokinetics , placebo , cmax , medicine , tolerability , ulcerative colitis , pharmacology , pharmacodynamics , gastroenterology , dosing , bioavailability , adverse effect , pathology , alternative medicine , disease
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 ), α 4 β 7 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 t max ranging between 2–10 days and a bioavailability between 82% and 99%. C max 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 t 1/2 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 α 4 β 7 RO showed an E C 50 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.