A dose‐adjusted, open‐label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis
Abstract Increased circulating histones correlate with sepsis severity and are a potential therapeutic target. Pre‐clinical studies showed benefit with a histone‐neutralizing polyanion molecule (STC3141). We aimed to investigate the safety, tolerability, and pharmacokinetics of STC3141 in critically...
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Wiley
2024-10-01
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| Series: | Pharmacology Research & Perspectives |
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| Online Access: | https://doi.org/10.1002/prp2.70015 |
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| author | Rinaldo Bellomo John Patava Ruth Van Lancker Nathalie Layios Marijke Peetermans Mark Plummer Rachid Attou Robert McNamara Andrew Udy Bradley Wibrow Adam Deane Edward Litton Marcel Tanudji Fuhong Su Zhang Zhong Linda Shi Li Ning |
| author_facet | Rinaldo Bellomo John Patava Ruth Van Lancker Nathalie Layios Marijke Peetermans Mark Plummer Rachid Attou Robert McNamara Andrew Udy Bradley Wibrow Adam Deane Edward Litton Marcel Tanudji Fuhong Su Zhang Zhong Linda Shi Li Ning |
| author_sort | Rinaldo Bellomo |
| collection | DOAJ |
| description | Abstract Increased circulating histones correlate with sepsis severity and are a potential therapeutic target. Pre‐clinical studies showed benefit with a histone‐neutralizing polyanion molecule (STC3141). We aimed to investigate the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis. We studied 26 patients with sepsis divided into four cohorts of one, five, ten, and ten subjects, respectively. We conducted a dose‐adjusted, open‐label study to determine the safety, tolerability, and pharmacokinetics of STC3141 administered as an IV infusion for up to 72 h, with rate adjusted to estimated creatinine clearance. Four steady‐state concentrations were targeted. Twenty of the 26 subjects (77%) in the study experienced at least one adverse event (AE). The most frequently reported study drug‐related AE was a mildly prolonged aPTT (four events). Only one AE (pulmonary hemorrhage) led to discontinuation of the drug. After excluding patients receiving renal replacement therapy (RRT) patients, clearance ranged from 3.3 to 4.2 L/h across cohorts and was essentially completely renal in nature. Half‐life values ranged from 5 to 7 h. The mean (±SD) terminal half‐life for non‐RRT subjects and for whom it was possible to calculate was approximately 9 (±4.77) h but increased to 19 (±7.94) h for subjects on RRT. Overall, 18 (69.2%) patients completed the study to day eight in the ICU, and 22 (84.6%) survived to 28 days. STC3141 administration appeared to have an acceptable degree of safety and tolerability and expected pharmacokinetics. Cautious, larger randomized efficacy trials in sepsis appear justified. |
| format | Article |
| id | doaj-art-da0fa7c176b54328a4be40fcea383aa3 |
| institution | OA Journals |
| issn | 2052-1707 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pharmacology Research & Perspectives |
| spelling | doaj-art-da0fa7c176b54328a4be40fcea383aa32025-08-20T02:16:33ZengWileyPharmacology Research & Perspectives2052-17072024-10-01125n/an/a10.1002/prp2.70015A dose‐adjusted, open‐label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsisRinaldo Bellomo0John Patava1Ruth Van Lancker2Nathalie Layios3Marijke Peetermans4Mark Plummer5Rachid Attou6Robert McNamara7Andrew Udy8Bradley Wibrow9Adam Deane10Edward Litton11Marcel Tanudji12Fuhong Su13Zhang Zhong14Linda Shi15Li Ning16Austin Hospital Heidelberg Victoria AustraliaGrand Medical Pty Ltd St Leonards New South Wales AustraliaUZ Brussel Brussels BelgiumC.H.U Liège, Sart Tilman Domaine Universitaire du Sart Tilman—B35 Liège 1 BelgiumUZ Lueven Leuven BelgiumRoyal Adelaide Hospital Adelaide South Australia AustraliaCHU Brugmann Brussels BelgiumRoyal Perth Hospital Perth Western Australia AustraliaAlfred Hospital Melbourne Victoria AustraliaSir Charles Gairdner Hospital Nedlands Western Australia AustraliaDepartment of Critical Care, Melbourne Medical School University of Melbourne Parkville Victoria AustraliaFiona Stanley Hospital Murdoch Western Australia AustraliaGrand Medical Pty Ltd St Leonards New South Wales AustraliaGrand Medical Pty Ltd St Leonards New South Wales AustraliaGrand Medical Pty Ltd St Leonards New South Wales AustraliaGrand Medical Pty Ltd St Leonards New South Wales AustraliaGrand Medical Pty Ltd St Leonards New South Wales AustraliaAbstract Increased circulating histones correlate with sepsis severity and are a potential therapeutic target. Pre‐clinical studies showed benefit with a histone‐neutralizing polyanion molecule (STC3141). We aimed to investigate the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis. We studied 26 patients with sepsis divided into four cohorts of one, five, ten, and ten subjects, respectively. We conducted a dose‐adjusted, open‐label study to determine the safety, tolerability, and pharmacokinetics of STC3141 administered as an IV infusion for up to 72 h, with rate adjusted to estimated creatinine clearance. Four steady‐state concentrations were targeted. Twenty of the 26 subjects (77%) in the study experienced at least one adverse event (AE). The most frequently reported study drug‐related AE was a mildly prolonged aPTT (four events). Only one AE (pulmonary hemorrhage) led to discontinuation of the drug. After excluding patients receiving renal replacement therapy (RRT) patients, clearance ranged from 3.3 to 4.2 L/h across cohorts and was essentially completely renal in nature. Half‐life values ranged from 5 to 7 h. The mean (±SD) terminal half‐life for non‐RRT subjects and for whom it was possible to calculate was approximately 9 (±4.77) h but increased to 19 (±7.94) h for subjects on RRT. Overall, 18 (69.2%) patients completed the study to day eight in the ICU, and 22 (84.6%) survived to 28 days. STC3141 administration appeared to have an acceptable degree of safety and tolerability and expected pharmacokinetics. Cautious, larger randomized efficacy trials in sepsis appear justified.https://doi.org/10.1002/prp2.70015histonesinflammatory responseNETssepsissmall molecule polyanion |
| spellingShingle | Rinaldo Bellomo John Patava Ruth Van Lancker Nathalie Layios Marijke Peetermans Mark Plummer Rachid Attou Robert McNamara Andrew Udy Bradley Wibrow Adam Deane Edward Litton Marcel Tanudji Fuhong Su Zhang Zhong Linda Shi Li Ning A dose‐adjusted, open‐label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis Pharmacology Research & Perspectives histones inflammatory response NETs sepsis small molecule polyanion |
| title | A dose‐adjusted, open‐label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis |
| title_full | A dose‐adjusted, open‐label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis |
| title_fullStr | A dose‐adjusted, open‐label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis |
| title_full_unstemmed | A dose‐adjusted, open‐label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis |
| title_short | A dose‐adjusted, open‐label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis |
| title_sort | dose adjusted open label pilot study of the safety tolerability and pharmacokinetics of stc3141 in critically ill patients with sepsis |
| topic | histones inflammatory response NETs sepsis small molecule polyanion |
| url | https://doi.org/10.1002/prp2.70015 |
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