ChanTest Introduces the CardioChannelGram and SaVety Assessment with a unique analysis of Cardiac Channel Panels that includes a risk assessment for Torsade de Pointes (TdP).
Determining the drug-induced inhibition of the cardiac hERG potassium channel is recommended by both the International Conference on Harmonization (ICH) and the US Food and Drug Administration (FDA) in order to predict delayed cardiac repolarization (DR) and cardiac risk. However, extending this determination to actually identifying drugs that may cause TdP, a serious polymorphic ventricular tachycardia, has been surprisingly challenging. The frequency of TdP may be <10-6 for non-cardiac drugs and cannot be reliably detected in early or late stage clinical trials. The risk of sudden death may become apparent only during marketing surveillance. QT prolongation has been chosen as a surrogate marker for TdP because TdP is always associated with a prolonged QT interval but the QT-TdP linkage is incomplete and the predictivity is weak. Impaired predictivity remains even under the minimal safety strategy laid out in the ICH S7B industry guidance. This guidance for evaluating delayed repolarization emphasizes the need for for assessing inhibition of the hERG potassium channel and QT prolongation in an in vivo assay. However, the S7B preclinical cardiac safety strategy may give internally discordant results and imperfect clinical predictivity making it difficult to determine a compound’s TdP risk.
In response to this, ChanTest has introduced the CardioChannelGram, logistic regression models that demonstrate that the prediction of cardiac risk. Predictivity is significantly better when quantitative drug effects on Cav1.2 and Nav1.5, in addition to hERG are measured. Cardiac risk can now be characterized earlier in development than ever before using automated patch clamp platforms.
Figure 1 below illustrates the potency of hERG as it correlates with the occurrence of being a Torsadogenic drug. A relationship is also present for Cav1.2 but for the Nav1.5 it does not appear quite so obvious.
Figure 1: Relationship between ETPC Indexes and the fraction of Torsadogenic drugs. Panels a, b and c show the fraction of +TdP drugs (P(+TdP)) present in each decade of -log transformed ETPC indexes for hERG, Cav1.2 and Nav1.5, respectively. The number of drugs included in the average is indicated next to each symbol. Bars indicate the standard error of the mean.
Figure 2: Terfenadine is concordant and verapamil is discordant with the notion that potent hERG blockers are torsadogenic because of it’s inhibition of Cav1.2. (a) IC50 values for hERG (red diamonds), Nav1.5 (blue squares) and Cav1.2 (blue circles) and the maximum effective free plasma concentration (asterisks). (b) Plot of the ETPC indexes for hERG (indicated at the interception of blue and orange segments), Cav1.2 (point at the end of the blue segment) and Nav1.5 (point at the end of the orange segment). Dashed lines indicate the region defined by Redfern’s ETPC index criteria of 30 for torsadogenic drugs. (c) The ETPC indexes for hERG, Cav1.2 and Nav1.5 channels of the 32 +TdP and 23 –TdP drugs included in the dataset.
Figure 3: The MICE approach results in better predictive TdP risk models. (left panel) Calculated Torsadogenic risk under Models 1 (hERG) and 4 (hERG + Nav1.5 + Cav1.2). Boxes indicated the 25, 50 and 75 percentile; whiskers indicate the 10 and 90 percentiles. Mean values (black diamonds). (right panel). ROC analysis of Model 1 and 4. The arrows indicate the cutoff point associated with the J index. The dashed line indicates the performance of a model that does not discriminate.
Figure 3 presents the results from two logistic fitting models where Model 1 using hERG inhibition results only and Model 4 uses hERG, Nav1.5 and Cav1.2. The predictive power of each model was evaluated using the likelihood ratio test. Leave-one-out cross validations were performed and each model’s accuracy was determined by comparing receiver–operating characteristics (ROC, sensitivity vs. 1-specificity). Models that include Nav1.5, Cav1.2 or both variables are statistically significant better predictors of TdP liability than the model that contains only hERG (Model 1). Model 1 had a ROC area under the curve (AUC) of 0.77 and Model 2, that includes hERG, Nav1.5 and Cav1.2 results, significantly improved accuracy with a ROC AUC of 0.91. Thus, Model 2 that incorporates a broader range of results in the CardioChannelGram™ (CCG™) is a much more robust nonclinical predictor of cardiac risk.
ChanTest scientists plug the IC50 values into these models to provide a SaVety Assessment risk profile for the compound in question. The report includes a comparison of the results to known compounds used in the study with similar CCG profiles. Therefore, the SaVety Assessment provides more confidence than ever regarding the risk profile of compounds before going into animal and/or human studies.