The Challenges of Predicting Drug-Induced QTc Prolongation in Humans

Abstract

The content of this manuscript derives from a Health and Environmental Sciences Institute (HESI) consortium with a focus to improve cardiac safety during drug development. A detailed literature review was conducted to evaluate the concordance between non-clinical repolarization assays and the clinical thorough QT (TQT) study (Vargas et al., 2015). FDA and HESI developed a joint database of non-clinical and clinical data, and a retrospective analysis of 150 anonymized drug candidates was reviewed to compare performance of three standard non-clinical assays with clinical TQT study findings as well as investigate mechanism(s) potentially responsible for apparent discrepancies identified. The non-clinical assays were functional (IKr) current block (hERG), action potential duration (APD), and QTc interval in animals (in vivo QTc). While these non-clinical assays demonstrated good specificity for predicting negative clinical QT prolongation, they had relatively poor sensitivity for predicting positive clinical QT prolongation (Park et al., 2018). After review, 28 discordant TQT-positive drugs were identified. This manuscript provides an overview of direct and indirect mechanisms responsible for QT prolongation and theoretical reasons for lack of concordance between clinical TQT studies and non-clinical assays. We examine six specific and discordant TQT-positive drugs as case examples. These were derived from the unique HESI/FDA database. We would like to emphasize some reasons for discordant data including, insufficient or inadequate non-clinical data, effects of the drug on other cardiac ion channels, and indirect and/or non-electrophysiological effects of drugs, including altered heart rate. We also outline best practices that were developed based upon our evaluation.

Predicting human cardiac QT alterations and pro-arrhythmic effects of compounds with a 3D beating heart-on-chip platform

“…In particular, current guidelines (ie, ICHS7B) impose that preclinical in vitro studies assess the drug-induced potassium channel blockage (ie, human ether-a-go-go-related gene—hERG assay) before performing telemetry in animals ( Garrido et al , 2020 ; Rock et al , 2009 ). Despite this approach has been demonstrated to effectively hamper potential torsadogenic drugs to reach the market, its lack of specificity often led to an inappropriate drug attrition and to a premature discontinuation of promising candidates, which while affecting potassium current do not cause TdP in humans ( Fermini et al , 2016 ; Valentin et al , 2022 ). Several evidences indeed proved that QT prolongation and the connected TdP risk in human can be mitigated by the simultaneous block of inward depolarizing currents (ie, calcium or late sodium), which balances the outward potassium current blockage, such as in the case of verapamil and ranolazine ( Johannesen, 2014 ; Redfern et al , 2003 ).…”

Testing the nonclinical Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm with an established anti‐seizure medication: Levetiracetam case study

“…Using the background reporting in the FAERS database as a reference, QT prolongation for LEV was not considered to have a higher reporting rate than expected. Although the primary mechanism of QTc prolongation/TdP is known to be hERG blockade, many risk factors can contribute, such as KCNH2 gene mutation, electrolyte disturbances, pre‐existing heart disease, bradycardia, or gender 29,30 …”

Homocysteine Levels and Clinical Outcomes in Schizophrenia—A Pilot Randomized Controlled Trial

“…53 Though olanzapine decreased homocysteine levels in group O patients, it showed cardiovascular toxicity, which may be attributed to other mechanisms of olanzapine like cyclic adenosine monophosphate, adrenergic alpha-1 blockade, eosinophilia, and orthostatic hypotension-induced tachycardia. 54-59…”

“…53 Though olanzapine decreased homocysteine levels in group O patients, it showed cardiovascular toxicity, which may be attributed to other mechanisms of olanzapine like cyclic adenosine monophosphate, adrenergic alpha-1 blockade, eosinophilia, and orthostatic hypotension-induced tachycardia. [54][55][56][57][58][59] Our study did not observe other unwanted symptoms such as gynecomastia, galactorrhea, menstrual irregularities, and sexual dysfunction. Neutropenia and agranulocytosis were also not observed in our study.…”