Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Fedyk, Eric R., Zhao, Lin, Koch, Annelize, Smithson, Glennda, Estevam, Jose, Chen, Grace, Lahu, Gezim, Roepcke, Stefan, Lin, Jianchang, Mclean, Lachy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
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
_version_ 1783550974869110784
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
work_keys_str_mv AT fedykericr safetytolerabilitypharmacokineticsandpharmacodynamicsoftheanticd38cytolyticantibodytak079inhealthysubjects
AT zhaolin safetytolerabilitypharmacokineticsandpharmacodynamicsoftheanticd38cytolyticantibodytak079inhealthysubjects
AT kochannelize safetytolerabilitypharmacokineticsandpharmacodynamicsoftheanticd38cytolyticantibodytak079inhealthysubjects
AT smithsonglennda safetytolerabilitypharmacokineticsandpharmacodynamicsoftheanticd38cytolyticantibodytak079inhealthysubjects
AT estevamjose safetytolerabilitypharmacokineticsandpharmacodynamicsoftheanticd38cytolyticantibodytak079inhealthysubjects
AT chengrace safetytolerabilitypharmacokineticsandpharmacodynamicsoftheanticd38cytolyticantibodytak079inhealthysubjects
AT lahugezim safetytolerabilitypharmacokineticsandpharmacodynamicsoftheanticd38cytolyticantibodytak079inhealthysubjects
AT roepckestefan safetytolerabilitypharmacokineticsandpharmacodynamicsoftheanticd38cytolyticantibodytak079inhealthysubjects
AT linjianchang safetytolerabilitypharmacokineticsandpharmacodynamicsoftheanticd38cytolyticantibodytak079inhealthysubjects
AT mcleanlachy safetytolerabilitypharmacokineticsandpharmacodynamicsoftheanticd38cytolyticantibodytak079inhealthysubjects