A Proof-of-Concept Evaluation of JTPc and Tp-Tec as Proarrhythmia Biomarkers in Preclinical Species: A Retrospective Analysis by an HESI-Sponsored Consortium
2019
Introduction:Based on the ICH S7B and E14 guidance documents,
QT interval(QTc) is used as the primary in vivo biomarker to assess the risk of drug-induced
torsades de pointes(TdP). Clinical and nonclinical data suggest that drugs that prolong the corrected QTc with balanced multiple
ion channelinhibition (most importantly the l-type calcium,
Cav1.2, and persistent or late inward sodium current,
Nav1.5, in addition to human Ether-a-go-go-Related Gene [
hERG] IKr or Kv11.1) may have limited proarrhythmic liability. The heart rate-corrected J to T-peak (JTpc) measurement in particular may be considered to discriminate selective
hERGblockers from multi-
ion channelblockers.Methods:Telemetry data from
Beagledogs given
dofetilide(0.3 mg/kg),
sotalol(32 mg/kg), and verapamil (30 mg/kg) orally and Cynomolgus monkeys given
medetomidine(0.4 mg/kg) orally were retrospectively analyzed for effects on QTca, JTpca, and T-peak to T-end covariate adjusted (Tpeca) interval using individual rate correction and super...
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