NEW ORLEANS, Nov. 04, 2026 (GLOBE NEWSWIRE) -- Dr. William J. Crumb Jr., Ph.D., President and CEO of Nova Research Laboratories, LLC, has collaborated with Dr. Andrew G. Edwards, Ph.D., Chief Research Scientist of Simula Research Laboratory in Oslo, Norway and COO of Organos in Berkely, California, on a new publication titled “Predicting thorough QT safety profile using hERG IC10 versus IC50.” Published in the Journal of Pharmacological and Toxicological Methods, the study examines an alternative approach to evaluating the potential cardiac safety risks of pharmaceutical compounds during drug development.
Dr. Crumb has an extensive history of conducting manual patch clamp studies in support of research aimed at improving the prediction of drug-induced cardiac risk during preclinical development. Combining his expertise in experimental electrophysiology with Dr. Edwards' expertise in computational physiology, the researchers evaluated whether a metric based on 10% inhibition of the hERG potassium channel (IC₁₀) could provide a more clinically relevant and potentially more practical alternative to the conventional IC₅₀-based approach.
Cardiac safety is a critical consideration in pharmaceutical development. Inhibition of the human ether-à-go-go-related gene (hERG) potassium channel can prolong the heart's QT interval, potentially increasing the risk of a life-threatening cardiac arrhythmia known as Torsade de Pointes (TdP). Assessment of hERG inhibition is therefore an important component of the nonclinical cardiac safety evaluations supporting Investigational New Drug (IND) applications.
Current ICH E14/S7B regulatory guidance relies on the determination of an IC₅₀, the concentration of a compound required to inhibit the hERG current by 50%, to calculate a safety margin relative to anticipated clinical exposure. Although the IC₅₀ is an established and valuable pharmacological metric, clinically meaningful QT prolongation often occurs at substantially lower levels of hERG inhibition.
The newly published study evaluated hERG inhibition data alongside clinical QTc measurements from 44 drug-dose combinations representing 30 pharmaceutical compounds. The researchers found that approximately 10% hERG inhibition corresponded to the clinically important threshold of 10 milliseconds of QTc prolongation. Specifically, 10.1% inhibition corresponded to the 10-millisecond threshold when evaluated using the upper confidence limit of clinical QTc prolongation, a key regulatory criterion.
Further analysis demonstrated that IC₁₀-based models offered improved discrimination of clinically relevant QTc prolongation at the upper confidence limit compared with IC₅₀-based models. The area under the receiver operating characteristic curve (AUC), a measure of predictive discrimination, increased from 0.898 for IC₅₀ to 0.951 for IC₁₀. Although this difference represented a statistical trend rather than a conventionally significant result, the findings support further evaluation of IC₁₀ as a basis for cardiac safety classification.
An additional advantage of IC₁₀ lies in its ability to account for differences in the shape of a compound's concentration-response curve. While an IC₅₀ identifies the concentration at which 50% inhibition occurs, it does not independently capture differences in the rate at which inhibition develops at lower concentrations. By incorporating the compound-specific Hill slope, IC₁₀ better reflects these differences in the concentration range more relevant to clinical exposure.
For compounds with shallow concentration-response curves, IC₅₀-based safety margins may underestimate QT liability, while compounds with steeper curves may be incorrectly flagged as presenting greater risk. Dr. Crumb and Dr. Edwards demonstrated that accounting for these differences through IC₁₀ could improve classification of compounds near the clinically relevant threshold for QT prolongation.
“These analyses suggest that important kinetic complexities of hERG-drug interactions can be captured by traditional Hill relationships applied to recordings made using human action potential waveforms,” commented Dr. Andrew G. Edwards, Ph.D.
Beyond its potential predictive advantages, IC₁₀ may also offer practical benefits for laboratories conducting preclinical hERG studies. For compounds that substantially inhibit hERG at relatively low concentrations, an IC₅₀ can typically be determined without difficulty. However, for compounds exhibiting weak hERG inhibition, establishing an IC₅₀ may require testing at concentrations far exceeding anticipated therapeutic exposure. At these elevated concentrations, factors such as limited compound solubility can complicate experimental evaluation or prevent reliable determination of an IC₅₀.
Because IC₁₀ represents a substantially lower level of inhibition, an IC₁₀-based assessment may reduce the need to achieve high concentrations that present experimental challenges. This potential practical benefit complements the study's findings regarding the clinical relevance of lower levels of hERG inhibition.
“This study indicates that hERG IC10 offers a direct index of QTc liabilities without the need for burdensome IC50-based measures and calculation of safety factors,” commented Dr. William J. Crumb Jr., Ph.D.
Together, these findings suggest an opportunity to refine the use of hERG inhibition data in nonclinical cardiac safety assessment. Rather than relying exclusively on a metric based on 50% inhibition, an approach incorporating IC₁₀ may provide a more direct relationship between experimental findings and clinically meaningful QT prolongation, while potentially reducing unnecessary experimental burdens.
Although further evaluation across larger and more diverse compound datasets is warranted, the study provides evidence supporting consideration of IC₁₀ in future discussions of cardiac safety assessment practices. Importantly, the findings do not diminish the broader pharmacological value of IC₅₀ but suggest that IC₁₀ may be particularly well suited to the specific task of predicting drug-induced QT prolongation.
Publication and Additional InformationFull publication:Edwards, A. G. & Crumb, W. J. (2026). Predicting thorough QT safety profile using hERG IC10 versus IC50. Journal of Pharmacological and Toxicological Methods, 140, 108564.https://doi.org/10.1016/j.vascn.2026.108564
Related research:Crumb, W. J., Vicente, J. et al. (2016). An evaluation of 30 clinical drugs against the comprehensive in vitro proarrhythmia assay (CiPA) proposed ion channel panel. Journal of Pharmacological and Toxicological Methods, 81, 251-262.https://www.sciencedirect.com/science/article/abs/pii/S105687191630017X?via%3Dihub
About Nova Research LaboratoriesNova Research Laboratories, LLC, based in New Orleans, Louisiana, specializes in ion channel electrophysiology and preclinical cardiac safety assessment. Through expert manual patch clamp techniques, including GLP-compliant hERG studies conducted in accordance with ICH S7B best practices, Nova supports pharmaceutical developers in evaluating cardiac electrophysiological liabilities and making informed decisions throughout drug development.
