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Safety, tolerability, pharmacokinetics and pharmacodynamics of the anti‐CD38 cytolytic antibody TAK‐079 in healthy subjects
AIMS: This investigation characterised tolerability, pharmacokinetics and pharmacodynamics of the anti‐CD38 antibody TAK‐079. METHODS: A randomised, double‐blind, placebo‐controlled trial of a single intravenous (i.v.) infusion or subcutaneous (s.c.) injection of TAK‐079 at escalating doses in healt...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319013/ https://www.ncbi.nlm.nih.gov/pubmed/32045493 http://dx.doi.org/10.1111/bcp.14241 |
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author | Fedyk, Eric R. Zhao, Lin Koch, Annelize Smithson, Glennda Estevam, Jose Chen, Grace Lahu, Gezim Roepcke, Stefan Lin, Jianchang Mclean, Lachy |
author_facet | Fedyk, Eric R. Zhao, Lin Koch, Annelize Smithson, Glennda Estevam, Jose Chen, Grace Lahu, Gezim Roepcke, Stefan Lin, Jianchang Mclean, Lachy |
author_sort | Fedyk, Eric R. |
collection | PubMed |
description | AIMS: This investigation characterised tolerability, pharmacokinetics and pharmacodynamics of the anti‐CD38 antibody TAK‐079. METHODS: A randomised, double‐blind, placebo‐controlled trial of a single intravenous (i.v.) infusion or subcutaneous (s.c.) injection of TAK‐079 at escalating doses in healthy subjects (n = 74), who were followed for 92 days postexposure. RESULTS: TAK‐079 was well tolerated. All adverse events were mild or moderate. There were no withdrawals, infusion, or injection site reactions over the tested i.v. and s.c. doses up to 0.06 and 0.6 mg kg(−1), respectively. At higher doses, transient cytokine level increases, following i.v. administration, coincided with reduction in CD38‐expressing cells; clinical symptoms included mild pyrexia, headache, and postural hypotension. Following an i.v. infusion of 0.06 mg kg(−1) TAK‐079, maximum observed serum concentration (C (max)) was 100.4 (%CV: 52) ng mL(−1), time to C (max) was the end of infusion and natural killer (NK_ cells were reduced 93.8 (±8.5) % from baseline levels. Following a s.c. injection of 0.6 mg kg(−1) TAK‐079, C (max) was 23.0 (%CV: 67) ng mL(−1) with time to C (max) of 24 (range 7.98–96.02) hours, and plasmablasts were subsequently reduced 93.4 (±8.8) % from predose levels. Serum immunoglobulin (Ig)M, IgA and IgG levels were reduced by 15–60% and had not returned to baseline levels within 78 days after administration at ≥0.3 mg kg(−1) s.c. Reductions in NK cells at 0.6 mg kg(−1) s.c. were approximately 2–3 times more durable than at 0.06 mg kg(−1) i.v. CONCLUSIONS: TAK‐079 was well tolerated and s.c. administration elicited more durable reductions in plasmablasts and NK cells. This plasmacytolytic profile could be useful for treating disorders caused by plasma or NK cells, malignant counterparts, and/or pathogenic antibodies. |
format | Online Article Text |
id | pubmed-7319013 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-73190132020-06-29 Safety, tolerability, pharmacokinetics and pharmacodynamics of the anti‐CD38 cytolytic antibody TAK‐079 in healthy subjects Fedyk, Eric R. Zhao, Lin Koch, Annelize Smithson, Glennda Estevam, Jose Chen, Grace Lahu, Gezim Roepcke, Stefan Lin, Jianchang Mclean, Lachy Br J Clin Pharmacol Original Articles AIMS: This investigation characterised tolerability, pharmacokinetics and pharmacodynamics of the anti‐CD38 antibody TAK‐079. METHODS: A randomised, double‐blind, placebo‐controlled trial of a single intravenous (i.v.) infusion or subcutaneous (s.c.) injection of TAK‐079 at escalating doses in healthy subjects (n = 74), who were followed for 92 days postexposure. RESULTS: TAK‐079 was well tolerated. All adverse events were mild or moderate. There were no withdrawals, infusion, or injection site reactions over the tested i.v. and s.c. doses up to 0.06 and 0.6 mg kg(−1), respectively. At higher doses, transient cytokine level increases, following i.v. administration, coincided with reduction in CD38‐expressing cells; clinical symptoms included mild pyrexia, headache, and postural hypotension. Following an i.v. infusion of 0.06 mg kg(−1) TAK‐079, maximum observed serum concentration (C (max)) was 100.4 (%CV: 52) ng mL(−1), time to C (max) was the end of infusion and natural killer (NK_ cells were reduced 93.8 (±8.5) % from baseline levels. Following a s.c. injection of 0.6 mg kg(−1) TAK‐079, C (max) was 23.0 (%CV: 67) ng mL(−1) with time to C (max) of 24 (range 7.98–96.02) hours, and plasmablasts were subsequently reduced 93.4 (±8.8) % from predose levels. Serum immunoglobulin (Ig)M, IgA and IgG levels were reduced by 15–60% and had not returned to baseline levels within 78 days after administration at ≥0.3 mg kg(−1) s.c. Reductions in NK cells at 0.6 mg kg(−1) s.c. were approximately 2–3 times more durable than at 0.06 mg kg(−1) i.v. CONCLUSIONS: TAK‐079 was well tolerated and s.c. administration elicited more durable reductions in plasmablasts and NK cells. This plasmacytolytic profile could be useful for treating disorders caused by plasma or NK cells, malignant counterparts, and/or pathogenic antibodies. John Wiley and Sons Inc. 2020-02-22 2020-07 /pmc/articles/PMC7319013/ /pubmed/32045493 http://dx.doi.org/10.1111/bcp.14241 Text en © 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles Fedyk, Eric R. Zhao, Lin Koch, Annelize Smithson, Glennda Estevam, Jose Chen, Grace Lahu, Gezim Roepcke, Stefan Lin, Jianchang Mclean, Lachy Safety, tolerability, pharmacokinetics and pharmacodynamics of the anti‐CD38 cytolytic antibody TAK‐079 in healthy subjects |
title | Safety, tolerability, pharmacokinetics and pharmacodynamics of the anti‐CD38 cytolytic antibody TAK‐079 in healthy subjects |
title_full | Safety, tolerability, pharmacokinetics and pharmacodynamics of the anti‐CD38 cytolytic antibody TAK‐079 in healthy subjects |
title_fullStr | Safety, tolerability, pharmacokinetics and pharmacodynamics of the anti‐CD38 cytolytic antibody TAK‐079 in healthy subjects |
title_full_unstemmed | Safety, tolerability, pharmacokinetics and pharmacodynamics of the anti‐CD38 cytolytic antibody TAK‐079 in healthy subjects |
title_short | Safety, tolerability, pharmacokinetics and pharmacodynamics of the anti‐CD38 cytolytic antibody TAK‐079 in healthy subjects |
title_sort | safety, tolerability, pharmacokinetics and pharmacodynamics of the anti‐cd38 cytolytic antibody tak‐079 in healthy subjects |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319013/ https://www.ncbi.nlm.nih.gov/pubmed/32045493 http://dx.doi.org/10.1111/bcp.14241 |
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