An evaluation of a supratherapeutic dose of inclisiran on cardiac repolarization in healthy volunteers : A phase I, randomized study
© 2022 Novartis Pharmaceuticals. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics..
Inclisiran is a small interfering RNA molecule that has been shown to provide an effective and sustained reduction in low-density lipoprotein cholesterol levels. This study aimed to determine whether a supratherapeutic dose of inclisiran affects cardiac repolarization and conduction in healthy volunteers. A phase I, randomized, double-blind, double-dummy, placebo- and positive-controlled, three-way crossover study was performed in 48 healthy volunteers. Volunteers were assigned to three treatments in a randomized sequence: a supratherapeutic dose of inclisiran sodium (900 mg), placebo, or moxifloxacin 400 mg as a positive control, with a minimum 7-day washout period between treatments. Continuous electrocardiogram monitoring was performed from >60 min before dosing until 48 h after dosing. Pharmacokinetics, pharmacodynamics, and safety were also assessed. Inclisiran, at a supratherapeutic dose, did not show a clinically significant effect on the QT interval (Fridericia correction formula [QTcF]; maximal placebo- and baseline-corrected change: 2.5 ms [90% confidence interval: 0.6, 4.5]) near the maximal plasma concentrations at 4 h. In addition, inclisiran did not show any effects on other electrocardiogram intervals or ST- and T-wave morphology. The positive control, moxifloxacin, demonstrated the expected changes in QTcF interval, validating the adequate sensitivity of the study. A supratherapeutic dose of inclisiran sodium (900 mg) had no effect on the QTcF interval or other electrocardiogram parameters, providing additional insight and reassurance regarding the safety profile of inclisiran.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
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| Enthalten in: |
Clinical and translational science - 15(2022), 11 vom: 01. Nov., Seite 2663-2672 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kallend, David [VerfasserIn] |
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| Links: |
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| Themen: |
9NEZ333N27 |
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| Anmerkungen: |
Date Completed 15.11.2022 Date Revised 24.01.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/cts.13391 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM347120156 |
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| 245 | 1 | 3 | |a An evaluation of a supratherapeutic dose of inclisiran on cardiac repolarization in healthy volunteers |b A phase I, randomized study |
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| 520 | |a © 2022 Novartis Pharmaceuticals. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. | ||
| 520 | |a Inclisiran is a small interfering RNA molecule that has been shown to provide an effective and sustained reduction in low-density lipoprotein cholesterol levels. This study aimed to determine whether a supratherapeutic dose of inclisiran affects cardiac repolarization and conduction in healthy volunteers. A phase I, randomized, double-blind, double-dummy, placebo- and positive-controlled, three-way crossover study was performed in 48 healthy volunteers. Volunteers were assigned to three treatments in a randomized sequence: a supratherapeutic dose of inclisiran sodium (900 mg), placebo, or moxifloxacin 400 mg as a positive control, with a minimum 7-day washout period between treatments. Continuous electrocardiogram monitoring was performed from >60 min before dosing until 48 h after dosing. Pharmacokinetics, pharmacodynamics, and safety were also assessed. Inclisiran, at a supratherapeutic dose, did not show a clinically significant effect on the QT interval (Fridericia correction formula [QTcF]; maximal placebo- and baseline-corrected change: 2.5 ms [90% confidence interval: 0.6, 4.5]) near the maximal plasma concentrations at 4 h. In addition, inclisiran did not show any effects on other electrocardiogram intervals or ST- and T-wave morphology. The positive control, moxifloxacin, demonstrated the expected changes in QTcF interval, validating the adequate sensitivity of the study. A supratherapeutic dose of inclisiran sodium (900 mg) had no effect on the QTcF interval or other electrocardiogram parameters, providing additional insight and reassurance regarding the safety profile of inclisiran | ||
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Clinical Trial, Phase I | |
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| 700 | 1 | |a Stoekenbroek, Robert |e verfasserin |4 aut | |
| 700 | 1 | |a He, YanLing |e verfasserin |4 aut | |
| 700 | 1 | |a Wijngaard, Peter |e verfasserin |4 aut | |
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