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Safety, Pharmacokinetics and Pharmacodynamics of DS-1040, in Combination with Thrombectomy, in Japanese Patients with Acute Ischemic Stroke

BACKGROUND AND OBJECTIVES: DS-1040 is a novel inhibitor of the activated form of thrombin-activatable fibrinolysis inhibitor that may have therapeutic potential in thromboembolic diseases, such as acute ischemic stroke (AIS) or pulmonary embolism. We undertook a Phase I clinical trial to investigate...

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Autores principales: Sakai, Nobuyuki, Takeuchi, Masataka, Imamura, Hirotoshi, Shimamura, Norihito, Yoshimura, Shinichi, Naito, Hiromichi, Kimura, Naoto, Masuo, Osamu, Hirotsune, Nobuyuki, Morita, Kenichi, Toyoda, Kazunori, Yamagami, Hiroshi, Ishihara, Hideyuki, Nakatsu, Takafumi, Miyoshi, Naoki, Suda, Miharu, Fujimoto, Shigeru
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8844171/
https://www.ncbi.nlm.nih.gov/pubmed/35061236
http://dx.doi.org/10.1007/s40261-021-01112-8
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author Sakai, Nobuyuki
Takeuchi, Masataka
Imamura, Hirotoshi
Shimamura, Norihito
Yoshimura, Shinichi
Naito, Hiromichi
Kimura, Naoto
Masuo, Osamu
Hirotsune, Nobuyuki
Morita, Kenichi
Toyoda, Kazunori
Yamagami, Hiroshi
Ishihara, Hideyuki
Nakatsu, Takafumi
Miyoshi, Naoki
Suda, Miharu
Fujimoto, Shigeru
author_facet Sakai, Nobuyuki
Takeuchi, Masataka
Imamura, Hirotoshi
Shimamura, Norihito
Yoshimura, Shinichi
Naito, Hiromichi
Kimura, Naoto
Masuo, Osamu
Hirotsune, Nobuyuki
Morita, Kenichi
Toyoda, Kazunori
Yamagami, Hiroshi
Ishihara, Hideyuki
Nakatsu, Takafumi
Miyoshi, Naoki
Suda, Miharu
Fujimoto, Shigeru
author_sort Sakai, Nobuyuki
collection PubMed
description BACKGROUND AND OBJECTIVES: DS-1040 is a novel inhibitor of the activated form of thrombin-activatable fibrinolysis inhibitor that may have therapeutic potential in thromboembolic diseases, such as acute ischemic stroke (AIS) or pulmonary embolism. We undertook a Phase I clinical trial to investigate the safety, pharmacokinetics, and pharmacodynamics of DS-1040 in Japanese patients who were eligible for thrombectomy following AIS. METHODS: The trial enrolled patients with AIS due to large vessel occlusion, who were planned for thrombectomy within 8 h of symptom onset. Subjects were randomized to receive a single intravenous infusion of placebo or DS-1040 (0.6, 1.2, 2.4 or 4.8 mg) in a sequential-cohort design. The primary endpoints were the incidence of intracranial hemorrhage (ICH) and major extracranial bleeding within 36 and 96 h, respectively, of treatment initiation. Treatment-emergent adverse events (TEAEs) and pharmacokinetic/pharmacodynamic parameters were also assessed. RESULTS: Nine patients received placebo and 32 patients received DS-1040. There were no cases of symptomatic ICH or major extracranial bleeding with either placebo or DS-1040 after 36 and 96 h. One patient, who received DS-1040 0.6 mg, experienced a subarachnoid hemorrhage that was considered to be drug-related. Three patients died (2 placebo, 1 DS-1040), but no deaths were adjudicated as study drug-related. In vivo exposure to DS-1040 increased in proportion to dosage, but no clear dose-response relationship was seen for D-dimer levels and thrombin-activatable fibrinolysis inhibitor activity. CONCLUSIONS: Single doses of DS-1040 0.6–4.8 mg were well tolerated in Japanese patients with AIS undergoing thrombectomy. CLINICAL TRIAL REGISTRATION NUMBER: NCT03198715; JapicCTI-163164. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40261-021-01112-8.
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spelling pubmed-88441712022-02-23 Safety, Pharmacokinetics and Pharmacodynamics of DS-1040, in Combination with Thrombectomy, in Japanese Patients with Acute Ischemic Stroke Sakai, Nobuyuki Takeuchi, Masataka Imamura, Hirotoshi Shimamura, Norihito Yoshimura, Shinichi Naito, Hiromichi Kimura, Naoto Masuo, Osamu Hirotsune, Nobuyuki Morita, Kenichi Toyoda, Kazunori Yamagami, Hiroshi Ishihara, Hideyuki Nakatsu, Takafumi Miyoshi, Naoki Suda, Miharu Fujimoto, Shigeru Clin Drug Investig Original Research Article BACKGROUND AND OBJECTIVES: DS-1040 is a novel inhibitor of the activated form of thrombin-activatable fibrinolysis inhibitor that may have therapeutic potential in thromboembolic diseases, such as acute ischemic stroke (AIS) or pulmonary embolism. We undertook a Phase I clinical trial to investigate the safety, pharmacokinetics, and pharmacodynamics of DS-1040 in Japanese patients who were eligible for thrombectomy following AIS. METHODS: The trial enrolled patients with AIS due to large vessel occlusion, who were planned for thrombectomy within 8 h of symptom onset. Subjects were randomized to receive a single intravenous infusion of placebo or DS-1040 (0.6, 1.2, 2.4 or 4.8 mg) in a sequential-cohort design. The primary endpoints were the incidence of intracranial hemorrhage (ICH) and major extracranial bleeding within 36 and 96 h, respectively, of treatment initiation. Treatment-emergent adverse events (TEAEs) and pharmacokinetic/pharmacodynamic parameters were also assessed. RESULTS: Nine patients received placebo and 32 patients received DS-1040. There were no cases of symptomatic ICH or major extracranial bleeding with either placebo or DS-1040 after 36 and 96 h. One patient, who received DS-1040 0.6 mg, experienced a subarachnoid hemorrhage that was considered to be drug-related. Three patients died (2 placebo, 1 DS-1040), but no deaths were adjudicated as study drug-related. In vivo exposure to DS-1040 increased in proportion to dosage, but no clear dose-response relationship was seen for D-dimer levels and thrombin-activatable fibrinolysis inhibitor activity. CONCLUSIONS: Single doses of DS-1040 0.6–4.8 mg were well tolerated in Japanese patients with AIS undergoing thrombectomy. CLINICAL TRIAL REGISTRATION NUMBER: NCT03198715; JapicCTI-163164. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40261-021-01112-8. Springer International Publishing 2022-01-21 2022 /pmc/articles/PMC8844171/ /pubmed/35061236 http://dx.doi.org/10.1007/s40261-021-01112-8 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by-nc/4.0/Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Original Research Article
Sakai, Nobuyuki
Takeuchi, Masataka
Imamura, Hirotoshi
Shimamura, Norihito
Yoshimura, Shinichi
Naito, Hiromichi
Kimura, Naoto
Masuo, Osamu
Hirotsune, Nobuyuki
Morita, Kenichi
Toyoda, Kazunori
Yamagami, Hiroshi
Ishihara, Hideyuki
Nakatsu, Takafumi
Miyoshi, Naoki
Suda, Miharu
Fujimoto, Shigeru
Safety, Pharmacokinetics and Pharmacodynamics of DS-1040, in Combination with Thrombectomy, in Japanese Patients with Acute Ischemic Stroke
title Safety, Pharmacokinetics and Pharmacodynamics of DS-1040, in Combination with Thrombectomy, in Japanese Patients with Acute Ischemic Stroke
title_full Safety, Pharmacokinetics and Pharmacodynamics of DS-1040, in Combination with Thrombectomy, in Japanese Patients with Acute Ischemic Stroke
title_fullStr Safety, Pharmacokinetics and Pharmacodynamics of DS-1040, in Combination with Thrombectomy, in Japanese Patients with Acute Ischemic Stroke
title_full_unstemmed Safety, Pharmacokinetics and Pharmacodynamics of DS-1040, in Combination with Thrombectomy, in Japanese Patients with Acute Ischemic Stroke
title_short Safety, Pharmacokinetics and Pharmacodynamics of DS-1040, in Combination with Thrombectomy, in Japanese Patients with Acute Ischemic Stroke
title_sort safety, pharmacokinetics and pharmacodynamics of ds-1040, in combination with thrombectomy, in japanese patients with acute ischemic stroke
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8844171/
https://www.ncbi.nlm.nih.gov/pubmed/35061236
http://dx.doi.org/10.1007/s40261-021-01112-8
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