ICH S7B In Vitro Assays Do Not Address Mechanisms of QT Prolongation for Peptides and Proteins - Data in Support of Not Needing Dedicated QT Studies.

Current cardiac safety testing focuses on detecting drug-induced QT prolongation as a surrogate for risk of Torsade de Pointes. The nonclinical strategy, described in International Conference on Harmonization (ICH) S7B, includes in vitro assessment of hERG block or ventricular repolarization delay and in vivo QT prolongation. Several studies have reported predictive values of ICH S7B results for clinical QT outcomes for small molecules; none has examined peptides and proteins other than monoclonal antibodies.

Mechanisms of QT prolongation by buprenorphine cannot be explained by direct hERG channel block.

Buprenorphine is a μ-opioid receptor (MOR) partial agonist used to manage pain and addiction. QTC prolongation that crosses the 10 msec threshold of regulatory concern was observed at a supratherapeutic dose in two thorough QT studies for the transdermal buprenorphine product BUTRANS®. Because QTC prolongation can be associated with Torsades de Pointes (TdP), a rare but potentially fatal ventricular arrhythmia, these results have led to further investigation of the electrophysiological effects of buprenorphine.

Heart Rate Correction of the J-to-Tpeak Interval.

Drug-induced changes of the J to T peak (JTp) and J to the median of area under the T wave (JT50) were reported to differentiate QT prolonging drugs that are predominant blockers of the delayed potassium rectifier current from those with multiple ion channel effects. Studies of drug-induced JTp/JT50 interval changes might therefore facilitate cardiac safety evaluation of new pharmaceuticals. It is not known whether formulas for QT heart rate correction are applicable to JTp and JT50 intervals.

Redefining Blood Pressure Assessment - The Role of the Ambulatory Blood Pressure Monitoring Study for Drug Safety.

According to models developed from large epidemiological studies, mean increases in systolic blood pressure of 2-3 mmHg can increase the risk of cardiovascular (CV) adverse events, especially in patients with a high risk for CV disease. There are new regulatory recommendations for the use of a safety ambulatory blood pressure monitoring (ABPM) study to assess the blood pressure (BP) effects of drugs used chronically. The ABPM study collects BP measurements over 24 hours at baseline and during treatment in patients with underlying CV risk.

Detection of T Wave Peak for Serial Comparisons of JTp Interval.

Electrocardiogram (ECG) studies of drug-induced prolongation of the interval between the J point and the peak of the T wave (JTp interval) distinguished QT prolonging drugs that predominantly block the delayed potassium rectifier current from those affecting multiple cardiac repolarisation ion channel currents. Since the peak of the T wave depends on ECG lead, a "global" T peak requires to combine ECG leads into one-dimensional signal in which the T wave peak can be measured. This study aimed at finding the optimum one-dimensional representation of 12-lead ECGs for the most stable JTp measurements.

Errors of Fixed QT Heart Rate Corrections Used in the Assessment of Drug-Induced QTc Changes.

The accuracy of studies of drug-induced QTc changes depends, among others, on the accuracy of heart rate correction of QT interval. It has been recognized that when a drug leads to substantial heart rate changes, fixed universal corrections cannot be used and that alternative methods such as subject-specific corrections established for each study participant need to be considered. Nevertheless, the maximum heart rate change that permits use of fixed correction with reasonable accuracy has not been systematically investigated.

Correction to: Implications of Individual QT/RR Profiles-Part 1: Inaccuracies and Problems of Population-Specific QT/Heart Rate Corrections.

The Open Access license, which previously read.

Correction to: Implications of Individual QT/RR Profiles-Part 2: Zero QTc/RR Correlations Do Not Prove QTc Correction Accuracy in Studies of QTc Changes.

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License which permits unrestricted use.

Assessment of Multi-Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study.

Balanced multi-ion channel-blocking drugs have low torsade risk because they block inward currents. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative proposes to use an in silico cardiomyocyte model to determine the presence of balanced block, and absence of heart rate corrected J-T (J-T c) prolongation would be expected for balanced blockers. This study included three balanced blockers in a 10-subject-per-drug parallel design; lopinavir/ritonavir and verapamil met the primary end point of ΔΔJ-T c upper bound < 10 ms, whereas ranolazine did not (upper bounds of 8.

Implications of Individual QT/RR Profiles-Part 1: Inaccuracies and Problems of Population-Specific QT/Heart Rate Corrections.

Introduction: Universal QT correction formulas are potentially problematic in corrected QT (QTc) interval comparisons at different heart rates. Instead of individual-specific corrections, population-specific corrections are occasionally used based on QT/RR data pooled from all study subjects.

Objective: To investigate the performance of individual-specific and population-specific corrections, a statistical modeling study was performed using QT/RR data of 523 healthy subjects.

Implications of Individual QT/RR Profiles-Part 2: Zero QTc/RR Correlations Do Not Prove QTc Correction Accuracy in Studies of QTc Changes.

Introduction: In studies of drug-induced corrected QT (QTc) changes, fixed universal heart rate (HR) corrections (e.g., the Fridericia correction) are potentially misleading when assessing the effects of drugs that change HR.

Correction: Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block.

[This corrects the article DOI: 10.1371/journal.pone.

Importance of QT/RR hysteresis correction in studies of drug-induced QTc interval changes.

QT/RR hysteresis and QT/RR adaptation are interlinked but separate physiological processes signifying how quickly and how much QT interval changes when heart rate changes, respectively. While QT interval duration is, as a rule, corrected for heart rate in terms of the QT/RR adaptation, the correction for QT/RR hysteresis is frequently omitted in studies of drug-induced QTc changes. This study used data from previously conducted thorough QT studies to investigate the extent of QTc errors caused by omitting the correction for QT/RR hysteresis, particularly in small clinical investigations.

Quantitative Understanding of QTc Prolongation and Gender as Risk Factors for Torsade de Pointes.

Several risk factors for development of a potentially fatal ventricular arrhythmia, torsade de pointes, have been observed, including female gender. However, in most investigations, only few torsade events were included and/or rarely were postdose heart rate corrected QT (QTc) measurements included, as a surrogate of drug exposure. We developed a multivariate logistic regression model using data from 22,214 patients (33% women) with 84 torsade events (56% women) to evaluate the relationship between risk factors for torsade using data from four anti-arrhythmic drug development programs.

Mechanistic Model-Informed Proarrhythmic Risk Assessment of Drugs: Review of the "CiPA" Initiative and Design of a Prospective Clinical Validation Study.

The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a mechanistic-based assessment of the proarrhythmic risk of drugs. CiPA proposes to assess a drug's effect on multiple ion channels and integrate the effects in a computer model of the human cardiomyocyte to predict proarrhythmic risk. Unanticipated or missed effects will be assessed with human stem cell-derived cardiomyocytes and electrocardiogram (ECG) analysis in early phase I clinical trials.

A novel ECG detector performance metric and its relationship with missing and false heart rate limit alarms.

Purpose: Performance of ECG beat detectors is traditionally assessed on long intervals (e.g.: 30min), but only incorrect detections within a short interval (e.

Electrocardiographic biomarkers to confirm drug's electrophysiological effects used for proarrhythmic risk prediction under CiPA.

The ECG plays a critical role in the thorough QT study. This clinical study is part of the assessment of proarrhythmic potential of drugs under the current regulatory paradigm. While the current paradigm has been successful in preventing drugs with unexpected QT prolongation or torsade risk from reaching the market, the focus on QT prolongation has likely resulted in potentially beneficial compounds with minimal torsade risk being dropped from development.

Heart rate dependency of JT interval sections.

Background: Little experience exists with the heart rate correction of J-Tpeak and Tpeak-Tend intervals.

Methods: In a population of 176 female and 176 male healthy subjects aged 32.3±9.

Common Genetic Variant Risk Score Is Associated With Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study.

Background: Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known.

Methods: We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs.

Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block.

Background: Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil).

Automated Algorithm for J-Tpeak and Tpeak-Tend Assessment of Drug-Induced Proarrhythmia Risk.

Background: Prolongation of the heart rate corrected QT (QTc) interval is a sensitive marker of torsade de pointes risk; however it is not specific as QTc prolonging drugs that block inward currents are often not associated with torsade. Recent work demonstrated that separate analysis of the heart rate corrected J-Tpeakc (J-Tpeakc) and Tpeak-Tend intervals can identify QTc prolonging drugs with inward current block and is being proposed as a part of a new cardiac safety paradigm for new drugs (the "CiPA" initiative).

Methods: In this work, we describe an automated measurement methodology for assessment of the J-Tpeakc and Tpeak-Tend intervals using the vector magnitude lead.

Comprehensive Translational Assessment of Human-Induced Pluripotent Stem Cell Derived Cardiomyocytes for Evaluating Drug-Induced Arrhythmias.

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the comprehensive in vitro proarrhythmia assay (CiPA). We studied the effects of 26 drugs and 3 drug combinations on 2 commercially available iPSC-CM types using high-throughput voltage-sensitive dye and microelectrode-array assays being studied for the CiPA initiative and compared the results with clinical QT prolongation and torsade de pointes (TdP) risk. Concentration-dependent analysis comparing iPSC-CMs to clinical trial results demonstrated good correlation between drug-induced rate-corrected action potential duration and field potential duration (APDc and FPDc) prolongation and clinical trial QTc prolongation.

An evaluation of 30 clinical drugs against the comprehensive in vitro proarrhythmia assay (CiPA) proposed ion channel panel.

Introduction: The Comprehensive in vitro Proarrhythmia Assay (CiPA) is intended to address the misidentification of drug-associated torsade de pointes risk based solely on hERG and QT data. This new paradigm will consist of four interrelated components, one of which is a panel consisting of six ion channels whose currents are important in both depolarization and repolarization of the cardiac action potential. This study examined the effects of 30 clinical drugs on these ion channels.

Universal Correction for QT/RR Hysteresis.

Introduction: Clinical pharmacology QT/QTc studies can be smaller if they more efficiently use the data generated.

Objective: The aim was to use large sets of electrocardiograms (ECGs) deposited at the US Food and Drug Administration to investigate the implications of heart rate measurement on the accuracy of QTc data.

Methods: Using the data of 80 thorough QT studies, we investigated whether placing study subjects in supine positions during short-term time points stabilizes heart rate (part I, based on 73 studies with 747,912 measured ECGs in 6786 healthy subjects) and whether heart rate measurements different from RR intervals captured simultaneously with QT intervals decrease QTc variability (part II, based on seven studies with 897,570 ECG measurements in 751 healthy subjects).

Computer simulations to investigate the causes of T-wave notching.

Drugs that cause strong hERG potassium channel block (e.g., dofetilide, quinidine) cause T-wave notching.