Dataset Information

Predicting QRS and PR interval prolongations in humans using nonclinical data.

ABSTRACT:

Background and purpose

Risk 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 approach

Four 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 results

Meaningful (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 implications

Small 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.

SUBMITTER: Bergenholm L

PROVIDER: S-EPMC5595766 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Publications

Predicting QRS and PR interval prolongations in humans using nonclinical data.

Bergenholm L L Parkinson J J Mettetal J J Evans N D ND Chappell M J MJ Collins T T

British journal of pharmacology 20170824 19

<h4>Background and purpose</h4>Risk 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.<h4>Experimental approach</h4>Four compounds that prolong QRS and/or PR (AZD1305, flecainide, quinidine and verapamil) were characterized using in vitro (sodium/calcium channels), in vivo (guine ...[more]

PMID: 28675424

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Project description:The PR interval on the electrocardiogram reflects atrial and atrioventricular nodal conduction time. The PR interval is heritable, provides important information about arrhythmia risk, and has been suggested to differ among human races. Genome-wide association (GWA) studies have identified common genetic determinants of the PR interval in individuals of European and Asian ancestry, but there is a general paucity of GWA studies in individuals of African ancestry. We performed GWA studies in African American individuals from four cohorts (n?=?6,247) to identify genetic variants associated with PR interval duration. Genotyping was performed using the Affymetrix 6.0 microarray. Imputation was performed for 2.8 million single nucleotide polymorphisms (SNPs) using combined YRI and CEU HapMap phase II panels. We observed a strong signal (rs3922844) within the gene encoding the cardiac sodium channel (SCN5A) with genome-wide significant association (p<2.5 x 10??) in two of the four cohorts and in the meta-analysis. The signal explained 2% of PR interval variability in African Americans (beta ?=?5.1 msec per minor allele, 95% CI ?=?4.1-6.1, p?=?3 x 10?²³). This SNP was also associated with PR interval (beta?=?2.4 msec per minor allele, 95% CI?=?1.8-3.0, p?=?3 x 10?¹?) in individuals of European ancestry (n?=?14,042), but with a smaller effect size (p for heterogeneity <0.001) and variability explained (0.5%). Further meta-analysis of the four cohorts identified genome-wide significant associations with SNPs in SCN10A (rs6798015), MEIS1 (rs10865355), and TBX5 (rs7312625) that were highly correlated with SNPs identified in European and Asian GWA studies. African ancestry was associated with increased PR duration (13.3 msec, p?=?0.009) in one but not the other three cohorts. Our findings demonstrate the relevance of common variants to African Americans at four loci previously associated with PR interval in European and Asian samples and identify an association signal at one of these loci that is more strongly associated with PR interval in African Americans than in Europeans.

Project description:BackgroundA prolonged PR interval is common among cardiac resynchronization therapy (CRT) candidates; however, the association between PR interval and outcomes is unclear, and the data are conflicting.MethodsWe conducted inverse probability weighted analyses of 26 451 CRT-eligible (ejection fraction ≤35, QRS ≥120 ms) patients from the National Cardiovascular Data Registry ICD Registry to assess the association between a prolonged PR interval (≥230 ms), receipt of CRT with defibrillator (CRT-D) versus implantable cardioverter defibrillator (ICD), and outcomes. We first tested the association between a prolonged PR interval and outcomes among patients stratified by device type. Next, we performed a comparative effectiveness analysis of CRT-D versus ICD among patients when stratified by PR interval. Using Medicare claims data, we followed up with patients up to 5 years for incident heart failure hospitalization or death.ResultsPatients with a PR≥230 ms (15%; n=4035) were older and had more comorbidities, including coronary artery disease, atrial arrhythmias, diabetes mellitus, and chronic kidney disease. After risk adjustment, a PR≥230 ms (versus PR<230 ms) was associated with increased risk of heart failure hospitalization or death among CRT-D (hazard ratio, 1.23; 95% confidence interval, 1.14-1.31; P<0.001) but not ICD recipients (hazard ratio, 1.08; 95% confidence interval, 0.97-1.20; P=0.17) (Pinteraction=0.043). CRT-D (versus ICD) was associated with lower rates of heart failure hospitalization or death among patients with PR<230 ms (hazard ratio, 0.79; 95% confidence interval, 0.73-0.85; P<0.001) but not PR≥230 ms (hazard ratio, 1.01; 95% confidence interval, 0.87-1.17; P=0.90) (Pinteraction=0.0025).ConclusionsA PR≥230 ms is associated with increased rates of heart failure hospitalization or death among CRT-D patients. The real-world comparative effectiveness of CRT-D (versus ICD) is significantly less among patients with a PR≥230 ms in comparison with patients with a PR<230 ms.

Dataset Information

Predicting QRS and PR interval prolongations in humans using nonclinical data.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

Predicting QRS and PR interval prolongations in humans using nonclinical data.

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