allopurinol and Long-QT-Syndrome

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 randomized, 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 h 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 eightfold 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.

Topics: Allopurinol; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Heart Rate; Humans; Long QT Syndrome; Moxifloxacin; Uric Acid

A QT/QTc study was conducted in compliance with ICH E14 guideline to evaluate the effects of a new xanthine oxidase inhibitor topiroxostat in Japanese healthy subjects. Forty-eight Japanese healthy subjects (males 24; females 24) received a single oral dose of topiroxostat (60 or 180 mg), moxifloxacin (400 mg) or placebo in a single-center, double-blind, four-period crossover design. Fridericia's formula (QTcF = QT/RR(0.33) ) was used as a primary method for QT-interval correction. The mean QTcF was prolonged by moxifloxacin, of which largest time-matched difference from placebo administration was 13.6 milliseconds with 90% confidence interval (CI) of 11.2 and 15.9 milliseconds at 4 hours post-dose. The mean QTcF was hardly affected by either dose of topiroxostat, of which largest time-matched difference from placebo administration was 2.9 milliseconds with 90% CI of 0.6 and 5.3 milliseconds at 4 hours post-dose for 60 mg, and 2.3 milliseconds with 90% CI of 0 and 4.7 milliseconds at 1 hour post-dose for 180 mg. The results were essentially the same in the sex subgroup analysis. Moxifloxacin can be used as a positive control for QT/QTc studies in Japanese subjects; and topiroxostat may not cause QT-interval prolongation in males as well as females.

Topics: Adult; Asian People; Cross-Over Studies; Double-Blind Method; Electrocardiography; Female; Fluoroquinolones; Humans; Long QT Syndrome; Male; Middle Aged; Moxifloxacin; Nitriles; Pyridines; Xanthine Oxidase; Young Adult