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), 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.

P008 Pharmacokinetics and pharmacodynamics in cynomolgus monkeys of AMG 181, a fully human anti a4 b7 antibody for treating inflammatory bowel disease W.-J. Pan1 *, S. Lear2, S. Patel1, P. Prince1, D. Doherty1, C.-Y. Tam1, C. Sheckler1, H. Hsu3, W. Rees2, A. Anderson4, J. Wisler5, K. Reynhardt6, J. Lynch7, J. Brandvig8, L. Wienkers1, D. Borie9. 1Amgen Inc., Pharmacokinetics and Drug Metabolism, Seattle, United States, 2Amgen Inc., Molecular Sciences and Computational Biology, Seattle, United States, 3Amgen Inc., Inflammation, Thousand Oaks, United States, 4Amgen Inc., Molecular Sciences and Computational Biology, Thousand Oaks, United States, 5Amgen Inc., Toxicology, Thousand Oaks, United States, 6Amgen Inc., Clinical Immunology, Seattle, United States, 7Charles River Laboratories, Preclinical Services, Reno, United States, 8Amgen Inc., Toxicology, Seattle, United States, 9Amgen Inc., Inflammation Clinical Research, Thousand Oaks, United States

P008 Pharmacokinetics and pharmacodynamics in cynomolgus monkeys of AMG 181, a fully human anti a4 b7 antibody for treating inflammatory bowel disease W.-J. Pan1 *, S. Lear2, S. Patel1, P. Prince1, D. Doherty1, C.-Y. Tam1, C. Sheckler1, H. Hsu3, W. Rees2, A. Anderson4, J. Wisler5, K. Reynhardt6, J. Lynch7, J. Brandvig8, L. Wienkers1, D. Borie9. 1Amgen Inc., Pharmacokinetics and Drug Metabolism, Seattle, United States, 2Amgen Inc., Molecular Sciences and Computational Biology, Seattle, United States, 3Amgen Inc., Inflammation, Thousand Oaks, United States, 4Amgen Inc., Molecular Sciences and Computational Biology, Thousand Oaks, United States, 5Amgen Inc., Toxicology, Thousand Oaks, United States, 6Amgen Inc., Clinical Immunology, Seattle, United States, 7Charles River Laboratories, Preclinical Services, Reno, United States, 8Amgen Inc., Toxicology, Seattle, United States, 9Amgen Inc., Inflammation Clinical Research, Thousand Oaks, United States

Pharmacokinetics (PK), Pharmacodynamics (PD), and Safety of Amg 181, a Fully Human Anti-α4β7 Antibody for Treating Inflammatory Bowel Diseases (IBD) Wei-Jian Pan, Barbara A. Sullivan, Christine M. Evangelista, David R. Doherty, Chi-Yan J. Tam, Sonal K. Patel, Peter J. Prince, Kai O. Reynhardt, William A. Rees, Hailing Hsu, Kefei Zhou, Wen Gu, Mark Yen, Christine A. Haller, Susanna Dodson, Zhigang Yu, Larry C. Wienkers, Dominique C. Borie

P225 Pharmacokinetics/pharmacodynamics and safety of AMG 181, a fully human anti-a 4 b 7 antibody for treating inflammatory bowel diseases (IBD) W.-J. Pan1 *, B. Sullivan2, C. Evangelista2, D. Doherty1, C.-Y. Tam1, S. Patel1, P. Prince1, K. Reynhardt3, W. Rees4, H. Hsu5, K. Zhou6, W. Gu7, M. Yen8, C. Haller9, S. Dodson10, Z. Yu10, L. Wienkers1, D. Borie11. 1Amgen Inc., Pharmacokinetics and Drug Metabolism, Seattle, United States, 2Amgen Inc., Clinical Immunology, Thousand Oaks, United States, 3Amgen Inc., Clinical Immunology, Seattle, United States, 4Amgen Inc., Molecular Sciences and Computational Biology, Seattle, United States, 5Amgen Inc., Inflammation, Thousand Oaks, United States, 6Amgen Inc., Biostatistics, San Francisco, United States, 7Amgen Inc., Biostatistics, Thousand Oaks, United States, 8Parexel Early Phase, California Clinical Trials Trials Medical Group, Glendale, United States, 9Amgen Inc., Regulatory, San Francisco, United States, 10Amgen Inc., Early Development, Thousand Oaks, United States, 11Amgen Inc., Inflammation Clinical Research, Thousand Oaks, United States