Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study
| العنوان: | Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study |
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| المؤلفون: | Daniel J. Dairaghi, Jay P. Powers, Juan C. Jaen, Trageen Baumgart, Yu Wang, Israel F. Charo, Ton Dang, Sarah Shugarts, Lisa Seitz, Daniel Johnson, Yibin Zeng, Lisa Lohr, Linda S. Ertl, Penglie Zhang, Pingchen Fan, Pirow Bekker, Manmohan Reddy Leleti, Thomas J. Schall, Shichang Miao |
| المصدر: | PLoS ONE PLoS ONE, Vol 11, Iss 10, p e0164646 (2016) |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Neutrophils, Physiology, Complement System, Nipecotic Acids, lcsh:Medicine, Phases of clinical research, Administration, Oral, Drug research and development, Monkeys, Pharmacology, Biochemistry, C5a receptor, White Blood Cells, Mice, Clinical trials, 0302 clinical medicine, Animal Cells, Immune Physiology, Medicine and Health Sciences, Medicine, lcsh:Science, Receptor, Mammals, Immune System Proteins, Multidisciplinary, Aniline Compounds, Phase I clinical investigation, Chemotaxis, Hematology, U937 Cells, Healthy Volunteers, Body Fluids, Cell Motility, Blood, Tolerability, Vertebrates, Cellular Types, Anatomy, Research Article, Primates, Immune Cells, Immunology, Mice, Transgenic, Blood Plasma, 03 medical and health sciences, Pharmacokinetics, In vivo, Potency, Animals, Humans, Receptor, Anaphylatoxin C5a, Blood Cells, business.industry, lcsh:R, Organisms, Biology and Life Sciences, Proteins, Correction, Cell Biology, Research and analysis methods, Macaca fascicularis, 030104 developmental biology, Clinical medicine, Immune System, Amniotes, lcsh:Q, business, 030217 neurology & neurosurgery, Ex vivo |
| الوصف: | The complement 5a receptor has been an attractive therapeutic target for many autoimmune and inflammatory disorders. However, development of a selective and potent C5aR antagonist has been challenging. Here we describe the characterization of CCX168 (avacopan), an orally administered selective and potent C5aR inhibitor. CCX168 blocked the C5a binding, C5a-mediated migration, calcium mobilization, and CD11b upregulation in U937 cells as well as in freshly isolated human neutrophils. CCX168 retains high potency when present in human blood. A transgenic human C5aR knock-in mouse model allowed comparison of the in vitro and in vivo efficacy of the molecule. CCX168 effectively blocked migration in in vitro and ex vivo chemotaxis assays, and it blocked the C5a-mediated neutrophil vascular endothelial margination. CCX168 was effective in migration and neutrophil margination assays in cynomolgus monkeys. This thorough in vitro and preclinical characterization enabled progression of CCX168 into the clinic and testing of its safety, tolerability, pharmacokinetic, and pharmacodynamic profiles in a Phase 1 clinical trial in 48 healthy volunteers. CCX168 was shown to be well tolerated across a broad dose range (1 to 100 mg) and it showed dose-dependent pharmacokinetics. An oral dose of 30 mg CCX168 given twice daily blocked the C5a-induced upregulation of CD11b in circulating neutrophils by 94% or greater throughout the entire day, demonstrating essentially complete target coverage. This dose regimen is being tested in clinical trials in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Trial Registration ISRCTN registry with trial ID ISRCTN13564773. |
| تدمد: | 1932-6203 1356-4773 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8e121ebccfd3be3946f666bdcc6c14a1Test https://pubmed.ncbi.nlm.nih.gov/30608991Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8e121ebccfd3be3946f666bdcc6c14a1 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 13564773 |
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