Concentration‐QT modelling shows no evidence of clinically significant QT interval prolongation with capivasertib at expected therapeutic concentrations
| العنوان: | Concentration‐QT modelling shows no evidence of clinically significant QT interval prolongation with capivasertib at expected therapeutic concentrations |
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| المؤلفون: | Veronika Voronova, Corina Dota, S. Y. Amy Cheung, Gaia Schiavon, Joanna Parkinson, Brijesh Maroj, Philip Delff, Marie Cullberg, Dinko Rekić |
| المصدر: | British Journal of Clinical Pharmacology. 88:858-864 |
| بيانات النشر: | Wiley, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Pharmacology, medicine.medical_specialty, Dose-Response Relationship, Drug, Potential risk, business.industry, Prolongation, Akt inhibitor, Positive correlation, QT interval, Electrocardiography, Long QT Syndrome, Pyrimidines, Therapeutic index, Heart Rate, Neoplasms, Internal medicine, Cardiology, Humans, Medicine, Pyrroles, Pharmacology (medical), In patient, Significant risk, business |
| الوصف: | Pharmacokinetics-matched digital electrocardiogram data (n = 503 measurements from 180 patients) collected in a first-in-human, multi-part, dose-escalation (from 80 to 800 mg) and dose expansion (at 480 mg) phase 1 study in patients with advanced solid malignancies, were used to assess potential risk of QT prolongation associated with the AKT inhibitor capivasertib. The relationship between plasma drug concentrations and baseline-adjusted Fridericia-corrected QT (ΔQTcF) values was estimated using a prespecified linear mixed-effects model. The model provided an unbiased reproduction of the experimental data set, estimating a small but positive correlation between capivasertib concentration and ΔQTcF. At the expected therapeutic dose (400 mg twice daily) the predicted mean ΔQTcF at the steady state maximum concentration was 3.97 ms with an upper limit of the 90% CI of 5.07 ms; below the 10 ms limit proposed by ICH E14 guidance. This analysis suggests that capivasertib is not expected to present a clinically significant risk for QT prolongation that is associated with pro-arrhythmic effects. |
| تدمد: | 1365-2125 0306-5251 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e215f8b5d116e504290ffedef3efbde9 https://doi.org/10.1111/bcp.15006 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....e215f8b5d116e504290ffedef3efbde9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 13652125 03065251 |
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