Verinurad does not prolong QTc interval: a thorough QT study using concentration–QTc modelling
| العنوان: | Verinurad does not prolong QTc interval: a thorough QT study using concentration–QTc modelling |
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| المؤلفون: | Joanna Parkinson, Corina Dota, Christian Källgren, Christer Gottfridsson, Magnus Bjursell, Shira Perl, Thomas Kӧrnicke, Dinko Rekić, Susanne Johansson |
| المصدر: | British Journal of Clinical Pharmacology. 89:1747-1755 |
| بيانات النشر: | Wiley, 2023. |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | Pharmacology, Pharmacology (medical) |
| الوصف: | This thorough QT/QTc (TQT) study was conducted to evaluate the risk of QT prolongation for verinurad when combined with allopurinol. Verinurad is a novel, urate anion exchanger 1 inhibitor that reduces serum urate levels by promoting urinary excretion of uric acid. It is co-administered with a xanthine oxidase inhibitor.The TQT study (NCT04256629) was a randomised, placebo-controlled, double-blind, three-period, crossover study, conducted in healthy volunteers. A total of 24 participants received single doses of verinurad 24 mg extended release, 40 mg immediate release formulation (both co-administered with allopurinol 300 mg), and matching placebos. The primary endpoint was baseline- and placebo-adjusted Fridericia-corrected QTcF interval (ΔΔQTcF) at the concentration of interest. A prespecified linear mixed-effects concentration-QTc model was used to estimate the primary endpoint. Time-matched 12-lead digital electrocardiograms and plasma concentrations were measured at baseline and up to 48 hours after dose in each participant.Estimated ΔΔQTcF at the highest clinically relevant scenario (76 ng/mL) was -2.7 msec (90% confidence interval [CI]: -4.6, -0.8). Furthermore, the upper 90% ΔΔQTcF CI was estimated to be below 10 msec at all observed verinurad concentrations. Supratherapeutic verinurad dose was used to achieve exposures 8-fold higher than the highest clinically relevant exposure, thus waiving the need for positive control.As the effect on ΔΔQTcF was below the threshold for regulatory concern (10 msec) at the supratherapeutic exposure, it can be concluded that verinurad and allopurinol treatment does not induce QTcF prolongation at the highest clinically relevant exposures. |
| تدمد: | 1365-2125 0306-5251 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4f3e1a5cd1f5ab34f80353d88d0e09a9 https://doi.org/10.1111/bcp.15637 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....4f3e1a5cd1f5ab34f80353d88d0e09a9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 13652125 03065251 |
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