Abstract:
PURPOSE:The International Conference on Harmonisation E14 guideline mandates an intensive cardiac safety evaluation in a clinical thorough QT study, typically in healthy subjects, for all new non-antiarrhythmic drugs with systemic bioavailability. This thorough QT study investigated the effects of therapeutic (2 mg) and supratherapeutic (10 mg) doses of siponimod (BAF312) on cardiac repolarization in healthy subjects. METHODS:The study was a randomized, double-blind, parallel-group, placebo- and moxifloxacin-controlled, multiple oral dose study. Eligible subjects were randomly assigned to 3 groups to receive siponimod (up-titration to 2 and 10 mg over 18 days), placebo (Days -1 to 18), or moxifloxacin 400 mg Days 10 and 18). Triplicate ECGs were extracted at prespecified time points from Holter ECGs recorded from 1 hour predose until 24 hours postdose at baseline and on-treatment assessment Days 10 and 18. The primary pharmacodynamic variable was the time-matched, placebo-corrected, baseline-adjusted mean QTcF (ΔΔQTcF) at steady-state conditions. In addition, the pharmacokinetic parameters of siponimod and its main circulating metabolite M3 and its metabolite M5 were evaluated. FINDINGS:Of the 304 enrolled subjects, 281 (92.4%) were included in the pharmacodynamic analysis and 270 (88.8%) completed the study. The upper bounds of the 2-sided 90% confidence intervals (CIs) for ΔΔQTcF at both siponimod doses were within the regulatory threshold of 10 milliseconds (ms) at all predefined on-treatment time points, with the absence of any dose-related effects. The highest observed upper limits of the 2-sided 90% CIs of 9.8 and 9.6 ms for therapeutic and supratherapeutic doses, respectively, were both observed at 3 hours postdose. No treatment-emergent QTc values >480 ms and no QTc increases of >60 ms from baseline were observed. Similar results were obtained with individualized heart rate correction of cardiac repolarization (QTcI). Assay validity was demonstrated by maximum ΔΔQTcF of >5 ms after 400 mg moxifloxacin on both on-treatment assessment days. The selected supratherapeutic dose produced approximately 5-fold higher exposures (Cmax and AUC) than the therapeutic dose, and was considered appropriate to investigate the effects of siponimod on QT/QTc at substantial multiples of the anticipated maximum therapeutic exposure. IMPLICATIONS:The findings provide evidence that siponimod is not associated with a significant arrhythmogenic potential related to QT prolongation.
journal_name
Clin Therjournal_title
Clinical therapeuticsauthors
Shakeri-Nejad K,Aslanis V,Veldandi UK,Mooney L,Pezous N,Brendani B,Juan A,Allison M,Perry R,Legangneux Edoi
10.1016/j.clinthera.2015.09.006subject
Has Abstractpub_date
2015-11-01 00:00:00pages
2489-2505.e2issue
11eissn
0149-2918issn
1879-114Xpii
S0149-2918(15)01131-5journal_volume
37pub_type
杂志文章,随机对照试验abstract:BACKGROUND:It has been reported that the efficacy of acute forms of nicotine replacement therapy, such as nicotine gum and lozenges, improves when sufficient quantities of medication are used. OBJECTIVE:This analysis examined whether adherence with daily nicotine patch wear was associated with improved rates of smokin...
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