Drug-induced QRS widening is primarily linked to inhibition of the sodium ion channel Na v1.5. In addition, treatment with conduction-slowing drugs (type 1C anti-arrhythmics) increased mortality in patients with structural heart disease in the Cardiac Arrhythmia Suppression Trial trials (Epstein et al., 1993). QRS complex duration corresponds to conduction through the ventricular myocardium and is a predictor of sudden cardiac death (Kurl et al., 2012). Much less is known of the nonclinical to clinical translation of drug-induced conduction slowing manifested as QRS and PR prolongations, despite their association with an increased risk of cardiovascular (CV) mortality and morbidity, especially in at risk populations (Nada et al., 2013). Numerous investigations provide insights for predicting risk of prolongation of the heart rate-corrected QT (QTc) interval (Jonker et al., 2005 Gintant, 2011 Chain et al., 2013 Parkinson et al., 2013). Identifying the effects on these biomarkers in nonclinical studies is vital for the progression of safe compounds into first clinical trials. Important biomarkers for heart function include the duration of key intervals in the ECG, such as QT, QRS and PR. Assuming broad applicability of these approaches to assess cardiovascular safety risk for non–arrhythmic drugs, this study provides a means of predicting human QRS/PR effects of new drugs from effects observed in nonclinical studies.Īdverse effects on vital processes involved in heart function are a major cause of drug withdrawal and late-stage attrition (Redfern et al., 2010 Laverty et al., 2011). Small changes in vitro and in vivo consistently translated to meaningful PR/QRS changes in humans across compounds. Meaningful QRS/PR changes in humans correlated with small effects in guinea pigs and dogs (QRS 2.3–4.6% and PR 2.3–10%), suggesting that worst-case human effects can be predicted by assuming four times greater effects at the same concentration from dog/guinea pig data. The in vitro model developed using AZD1305 successfully predicted QRS/PR effects for the remaining drugs. Meaningful (10%) human QRS/PR effects correlated with low levels of in vitro Na v1.5 block (3–7%) and Ca v1.2 binding (13–21%) for all compounds. Concentration-matched translational relationships were developed based on in vitro and in vivo modelling, and the in vitro to clinical translation of AZD1305 was quantified using an in vitro model. Experimental Approachįour compounds that prolong QRS and/or PR (AZD1305, flecainide, quinidine and verapamil) were characterized using in vitro (sodium/calcium channels), in vivo (guinea pigs/dogs) and clinical data. Understanding the quantitative translation of these studies to the clinical situation enables improved risk assessment in the nonclinical phase. Risk of cardiac conduction slowing (QRS/PR prolongations) is assessed prior to clinical trials using in vitro and in vivo studies.
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