Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea‐pig model

Abstract

Background and purpose: Drug-induced prolongation of the QT interval can lead to torsade de pointes, a life-threatening ventricular arrhythmia. Finding appropriate assays from among the plethora of options available to predict reliably this serious adverse effect in humans remains a challenging issue for the discovery and development of drugs. The purpose of the present study was to develop and verify a reliable and relatively simple approach for assessing, during preclinical development, the propensity of drugs to prolong the QT interval in humans. Experimental approach: Sixteen marketed drugs from various pharmacological classes with a known incidence-or lack thereof-of QT prolongation in humans were examined in hERG (human ether a-go-go-related gene) patch-clamp assay and an anaesthetized guinea-pig assay for QT prolongation using specific protocols. Drug concentrations in perfusates from hERG assays and plasma samples from guinea-pigs were determined using liquid chromatography-mass spectrometry. Key results: Various pharmacological agents that inhibit hERG currents prolong the QT interval in anaesthetized guinea-pigs in a manner similar to that seen in humans and at comparable drug exposures. Several compounds not associated with QT prolongation in humans failed to prolong the QT interval in this model. Conclusions and implications: Analysis of hERG inhibitory potency in conjunction with drug exposures and QT interval measurements in anaesthetized guinea-pigs can reliably predict, during preclinical drug development, the risk of human QT prolongation. A strategy is proposed for mitigating the risk of QT prolongation of new chemical entities during early lead optimization.

Early drug development: assessment of proarrhythmic risk and cardiovascular safety

“…Alternatively, Gintant et al have shown that a hERG safety margin of 45-fold between the IC 50 dose and the free plasma drug concentration predicts the absence of a QT effect >5 ms with a sensitivity of 64% and a specificity of 88%, highlighting the relative weakness of this assay for truly predicting QTc prolongation clinically [18]. Interpretation of these results is further complicated by the lack of standards for the hERG patch clamp assay and the associated variability of results observed between different laboratories which may be as high as a 20-fold difference in IC 50 values for a specific drug [19]. Further contributing to this weakness is that hERG current block is influenced by the type of mammalian cell line employed, the temperature of the experimental preparation, the configuration of the potassium channel which may be open or closed during testing, and the stimulation frequency and protocol used [20].…”

Development and Comparison of hERG Blocker Classifiers: Assessment on Different Datasets Yields Markedly Different Results

“…[7] Moreover, numerous ligand-based QSAR models for predicting hERG inhibition have been developed, many of which are reviewed in recent articles by Thai et al [8,9] Both regression models, designed to directly predict hERG IC 50 values, i.e. the half-maximal inhibitory concentration, [5] typically giving 50 % channel blockade in electrophysiological assays, [10,11] and classification models have been developed. Here, our focus is on classification models.…”

“…Similarly, Yao et al [11] proposed a safety margin of 300 : 1 (hERG IC 50 : maximum unbound plasma concentration) to separate drugs causing QT interval prolongation and TdP and those inducing neither cardiac disorder.…”

“…Furthermore, compounds with an IC 50 < 1 mM usually exhibit QT interval prolongation in in vivo assays, and their development is typically discontinued. [11] These thresholds are also accepted as reasonable safety heuristics within AstraZeneca. [4] …”

Pre-clinical QT Risk Assessment in Pharmaceutical Companies - Issues of Current QT Risk Assessment -

“…Meanwhile, the ionic mechanisms of repolarization in adult rats and mice differ from larger species including humans, so that use of these species is not considered appropriate. Although there is clear preference for safety pharmacology studies to be performed in conscious free-moving animals in the ICH S7A guideline, anesthetized (e.g., isoflurane or halothane) animals such as dogs and guinea pigs are generally regarded as more useful because of higher sensitive to drug-induced QT prolongation than conscious animals, and better control of the heart rate (e.g., through cardiac pacing at a constant rate) (Tashibu et al, 2005;Yao et al, 2008).…”