In:
British Journal of Clinical Pharmacology, Wiley, Vol. 78, No. 6 ( 2014-12), p. 1315-1333
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0306-5251
,
1365-2125
DOI:
10.1111/bcp.2014.78.issue-6
Language:
English
Publisher:
Wiley
Publication Date:
2014
detail.hit.zdb_id:
1498142-7
SSG:
15,3
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