Dataset Information

Clinical pharmacology of AMG 181, a gut-specific human anti-?4?7 monoclonal antibody, for treating inflammatory bowel diseases.

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.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), ?4 ?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.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 ?-phase t1/2 was 31 (range 20-48) days. Target-mediated disposition occurred at serum AMG 181 concentrations of less than 1??g?ml(-1) . The PD effect on ?4 ?7 RO showed an EC50 of 0.01??g?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.AMG 181 has PK/PD, safety, and effect profiles suitable for further testing in subjects with inflammatory bowel diseases.

SUBMITTER: Pan WJ

PROVIDER: S-EPMC4256621 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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

Pan Wei-Jian WJ Köck Kathleen K Rees William A WA Sullivan Barbara A BA Evangelista Christine M CM Yen Mark M Andrews Jane M JM Radford-Smith Graham L GL Prince Peter J PJ Reynhardt Kaz O KO Doherty David R DR Patel Sonal K SK Krill Christine D CD Zhou Kefei K Shen Jing J Smith Lynn E LE Gow Jason M JM Lee Jonathan J Treacy Anthony M AM Yu Zhigang Z Platt Virginia M VM Borie Dominic C DC

British journal of clinical pharmacology 20141201 6

<h4>Aims</h4>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.<h4>Methods</h4>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 AM ...[more]

PMID: 24803302

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Project description:The gut microbiome is of utmost importance to human health. While a healthy microbiome can be represented by a variety of structures, its functional capacity appears to be more important. Gene content of the community can be assessed by "shotgun" metagenomics, but this approach is still too expensive. High-throughput amplicon-based surveys are a method of choice for large-scale surveys of links between microbiome, diseases, and diet, but the algorithms for predicting functional composition need to be improved to achieve good precision. Here we show how feature engineering based on microbial phenotypes, an advanced method for functional prediction from 16S rRNA sequencing data, improves identification of alterations of the gut microbiome linked to the disease. We processed a large collection of published gut microbial datasets of inflammatory bowel disease (IBD) patients to derive their community phenotype indices (CPI)-high-precision semiquantitative profiles aggregating metabolic potential of the community members based on genome-wide metabolic reconstructions. The list of selected metabolic functions included metabolism of short-chain fatty acids, vitamins, and carbohydrates. The machine-learning approach based on microbial phenotypes allows us to distinguish the microbiome profiles of healthy controls from patients with Crohn's disease and from ones with ulcerative colitis. The classifiers were comparable in quality to conventional taxonomy-based classifiers but provided new findings giving insights into possible mechanisms of pathogenesis. Feature-wise partial dependence plot (PDP) analysis of contribution to the classification result revealed a diversity of patterns. These observations suggest a constructive basis for defining functional homeostasis of the healthy human gut microbiome. The developed features are promising interpretable candidate biomarkers for assessing microbiome contribution to disease risk for the purposes of personalized medicine and clinical trials.

Dataset Information

Clinical pharmacology of AMG 181, a gut-specific human anti-?4?7 monoclonal antibody, for treating inflammatory bowel diseases.

Publications

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

Similar Datasets

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