Predicting QRS and PR interval prolongations in humans using nonclinical data

Abstract

BACKGROUND AND PURPOSERisk of cardiac conduction slowing (QRS/PR prolongations) is assessed prior to clinical trials using in vitro and in vivo studies. Understanding the quantitative translation of these studies to the clinical situation enables improved risk assessment in the nonclinical phase. EXPERIMENTAL APPROACHFour 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. 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. KEY RESULTSMeaningful (10%) human QRS/PR effects correlated with low levels of in vitro Na v 1.5 block (3-7%) and Ca v 1.2 binding (13-21%) for all compounds. The in vitro model developed using AZD1305 successfully predicted QRS/PR effects for the remaining drugs. 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. CONCLUSION AND IMPLICATIONSSmall changes in vitro and in vivo consistently translated to meaningful PR/QRS changes in humans across compounds. 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. AbbreviationsFTIM, first time in man; hCav1.2, human cardiac calcium channel; hNav1.5, human cardiac sodium channel; rCav1.2, rat cardiac calcium channel; PD, pharmacodynamic; PK, pharmacokinetic; PPB, plasma protein binding; QTc, heart ratecorrected QT

Computational translation of drug effects from animal experiments to human ventricular myocytes

“…www.nature.com/scientificreports www.nature.com/scientificreports/ animal biomarkers (see e.g. [34][35][36][37][38] ). However, no mechanistic relationship has, to date, been derived to examine how drug candidates may affect human and animal cardiomyocytes differentially.…”

Telemetered common marmosets is useful for the assessment of electrocardiogram parameters changes induced by multiple cardiac ion channel inhibitors

“…Plasma exposure-dependent PR prolongation by verapamil is considered due to Cav1.2 inhibition because verapamil has strong inhibitory potentials to hERG and Cav1.2 and the other hERG positive compounds except for flecainide did not induce PR prolongation at QTc prolonged dose. In addition, the relationship between PR prolongation and estimated Cav1.2 inhibition in humans was demonstrated using verapamil (Bergenholm et al, 2017). The flecainide-induced PR prolongation is possible to be related to dual effects of Nav1.5 and Cav1.2 inhibitions because flecainide has both Nav1.5 and Cav1.2 inhibitory potentials.…”

“…PR prolongation has been reported to be related to Nav1.5 and Cav1.2 inhibitions (Priest and McDermott, 2015;Bergenholm et al, 2017). Plasma exposure-dependent PR prolongation by verapamil is considered due to Cav1.2 inhibition because verapamil has strong inhibitory potentials to hERG and Cav1.2 and the other hERG positive compounds except for flecainide did not induce PR prolongation at QTc prolonged dose.…”

“…Flecainide-and quinidine-induced QRS widening is suggested to be related to Nav1.5 channel inhibition, because the compounds have relatively strong Nav1.5 inhibitory potential (known as Class I arrhythmic drugs) and the relationship between QRS widening and estimated Nav1.5 inhibition in humans was demonstrated using flecainide and quinidine (Bergenholm et al, 2017). The plasma exposure levels of flecainide or quinidine reached at 4.4 μM or 0.7 μM, respectively, which were similar to and one twentieth at their IC 50 for Nav1.5, respectively.…”

“…Since it is known that drugs that induce TdP in humans, cause the prolongation of corrected QT interval (QTc) through the inhibition of human ether-a-go-go-related gene (hERG) channel (Redfern et al, 2003), drug candidates in vitro hERG inhibition is commonly assessed in an early stage of drug development to screen out proarrhythmogenic compounds. In addition to hERG, other cardiac ion channels, such as voltage-dependent sodium channel type 1.5 (Nav1.5) and voltage-dependent calcium channel type 1.2 (Cav1.2), also contribute to proarrhythmic liability, suggesting that Nav1.5 inhibition results in PR prolongation and QRS widening, and Cav1.2 inhibition causes PR prolongation and QTc shortening (Priest and McDermott, 2015;Bergenholm et al, 2017;Isobe et al, 2018). Although in vitro and in silico assay systems that use in vitro data of multiple cardiac ion channel inhibitory potential have been reported as challenges for TdP risk prediction (Kramer et al, 2013;O'Hara et al, 2011;Li et al, 2019), in vivo studies are considered as the definitive approach.…”