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Validation and Clinical Utility of the hERG IC50:Cmax Ratio to Determine the Risk of Drug-Induced Torsades de
David F Lehmann1, William D Eggleston2,3, Dongliang Wang4
1Department of Medicine, SUNY Upstate Medical University, Syracuse, New York.
Insights
The hERG IC50:Cmax ratio effectively predicts drug-induced torsades de pointes (TdP) risk. This validated ratio aids clinical decisions for safer drug selection, minimizing TdP events.
Area of Science:
- Pharmacology
- Cardiology
- Drug Safety
Background:
- Current methods using corrected QT (QTc) interval on ECG lack sensitivity and specificity for predicting drug-induced torsades de pointes (TdP).
- The ratio of hERG channel inhibitory concentration (hERG IC50) to peak unbound drug concentration (Cmax) is a preclinical screening tool for TdP risk.
Purpose of the Study:
- To validate the predictive utility of the hERG IC50:Cmax ratio for TdP risk by correlating it with observed TdP incidence in clinical settings.
Main Methods:
- Literature search of Medline (1966-2017) for hERG IC50 and Cmax data in antihistamine, fluoroquinolone, and antipsychotic drug classes.
- Inclusion of TdP cases with ECG-confirmed QTc prolongation and normal electrolytes, excluding drug interactions and prior rhythm disturbances.
- Estimation of drug exposure using manufacturer annual revenues and application of the Meta-Analysis of Observational Studies in Epidemiology checklist.
Main Results:
- The hERG IC50:Cmax ratio demonstrated a significant correlation with TdP risk (p<0.0001).
- A ratio of 80 was associated with a relative risk (RR) of 1.0, defining negligible risk.
- Specific drugs like olanzapine and ziprasidone showed RR comparable to loratadine and ciprofloxacin, respectively, while astemizole, risperidone, haloperidol, and thioridazine had RR > 50.
Conclusions:
- The hERG IC50:Cmax ratio is validated as a predictor of TdP incidence for culprit drugs.
- This validated ratio supports its use in clinical decision-making for drug selection when TdP risk is a concern.
Background:
Use of the QT interval corrected for heart rate (QTc) on the electrocardiogram (ECG) to predict torsades de pointes (TdP) risk from culprit drugs is neither sensitive nor specific. The ratio of the half-maximum inhibitory concentration of the hERG channel (hERG IC50) to the peak serum concentration of unbound drug (Cmax ) is used during drug development to screen out chemical entities likely to cause TdP.
Purpose:
To validate the use of the hERG IC50:Cmax ratio to predict TdP risk from a culprit drug by its correlation with TdP incidence.
Data Sources:
Medline (between 1966 and March 2017) was accessed for hERG IC50 and Cmax values from the antihistamine, fluoroquinolone, and antipsychotic classes to identify cases of drug-induced TdP. Exposure to a culprit drug was estimated from annual revenues reported by the manufacturer.
Study Selection:
Inclusion criteria for TdP cases were provision of an ECG tracing that demonstrated QTc prolongation with TdP and normal serum values of potassium, calcium, and magnesium. Cases reported in patients with a prior rhythm disturbance and those involving a drug interaction were excluded.
Data Extraction And Synthesis:
The Meta-Analysis of Observational Studies in Epidemiology checklist was used for epidemiological data extraction by two authors.
Main Outcome And Measure:
Negligible risk drugs were defined by an hERG IC50:Cmax ratio that correlated with less than a 5% chance of one TdP event for every 100 million exposures (relative risk [RR] 1.0).
Results:
The hERG IC50:Cmax ratio correlated with TdP risk (0.312; 95% confidence interval 0.205-0.476, p<0.0001), a ratio of 80 (RR 1.0). The RR from olanzapine is on par with loratadine; ziprasidone is comparable with ciprofloxacin. Drugs with an RR greater than 50 include astemizole, risperidone, haloperidol, and thioridazine.
Conclusions:
The hERG IC50:Cmax ratio was correlated with TdP incidence for culprit drugs. This validation provides support for the potential use of the hERG IC50:Cmax ratio for clinical decision making in instances of drug selection where TdP risk is a concern.
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