Novel electrocardiographic biomarkers for proarrhythmic assessment of drugs
- Autores: Jose Vicente Ruiz
- Directores de la Tesis: David G Strauss (dir. tes.), Esther Pueyo Paules (dir. tes.)
- Lectura: En la Universidad de Zaragoza ( España ) en 2016
- Idioma: español
- Tribunal Calificador de la Tesis: A. Bayés de Luna (presid.), Violeta Monasterio Bazán (secret.), Michael Ringborn (voc.), Beatriz Ana Trenor Gomis (voc.), Jean-Phillippe Couderc (voc.)
- Programa de doctorado: Programa de Doctorado en Ingeniería Biomédica por la Universidad Politécnica de Catalunya y la Universidad de Zaragoza
- Materias:
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- Resumen
In the 1990s there was an increasing recognition that non-cardiac drugs could cause torsade de pointes (torsade), a potentially fatal ventricular arrhythmia that disproportionately affects women. Most drugs that cause torsade block the human ether-à-go-go related gene (hERG) potassium channel and prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG). This resulted in fourteen drugs removed from the market worldwide due to potential for QTc prolongation and/or torsade. In addition, the extreme focus on drug-induced effects on the QTc interval and hERG potassium channel has likely led to drugs being inappropriately dropped from development. For example, QTc prolonging drugs with minimal torsade risk like ranolazine or verapamil may have not reached the market under the current regulatory paradigm. The minimal risk for torsade with these drugs is likely because they block inward currents (e.g. L-type calcium with verapamil or late sodium with ranolazine) in addition to hERG.
Through use of novel ECG morphology biomarkers and computer simulations, this thesis assesses whether there are sex differences in drug-induced changes in ventricular repolarization that can explain sex differences in drug-induced proarrhythmic risk. Moreover, the main goal of this thesis is to identify ECG biomarkers that can be used to differentiate drug-induced multi-ion channel current effects of relevance for torsade risk.
The thesis is composed of Studies I - V. Through an analysis of baseline ECGs from 30 thorough QT studies, Study I shows that age and sex differences in QTc are due to differences in the heart rate corrected J-Tpeak interval (J-Tpeakc). In silico simulations suggest that these differences are likely due to testosterone effects on the L-type calcium current.
Study II presents a sex-specific analysis of intravenous quinidine-induced changes on ventricular repolarization. Results show that women are not more sensitive to quinidine-induced effects on QTc and Tpeak-Tend than men. Moreover, sex differences previously reported in the literature on data in Study II were due to a delay between plasma drug concentration and ECG changes (hysteresis), which was present in men but not in women.
The next two studies present a comprehensive assessment of ECG morphology biomarkers in a randomized clinical trial of dofetilide, quinidine, ranolazine and verapamil. Study III shows that there is a strong exposure-response relationship between selective hERG potassium channel blocking drugs and T-wave morphology changes. Multichannel blocking drugs still have a exposure-response relationship with T-wave morphology, in some cases having greater T-wave morphology changes at equivalent amounts of QTc prolongation compared with selective hERG potassium channel block. Sex specific analysis (Study IV) shows no sex differences in QTc prolongation induced by dofetilide, quinidine and ranolazine. Moreover, no systematic sex differences of other drug-induced ECG biomarker changes are present. Results of these studies suggest that J-Tpeakc is the only biomarker that provides independent information from QTc to differentiate multichannel blocking drugs from selective hERG potassium channel blocking drugs.
Study V extends Study III with an analysis of data from a prospective clinical trial of moxifloxacin, dofetilide and dofetilide combined with either mexiletine or lidocaine. This study shows that drug-induced ECG signatures of selective hERG potassium channel block (moxifloxacin, dofetilide) and multichannel block (dofetilide + mexiletine, dofetilide + lidocaine, ranolazine) are reproducible and consistent. Analysis ranking ECG biomarkers by their ability to detect presence of inward current block shows that J-Tpeakc is the best of all studied ECG biomarkers for detecting late sodium current block.
The studies in this thesis suggest that an integrated assessment of J-Tpeakc and QTc can differentiate multichannel block from selective hERG potassium channel block on the ECG. This is important because this type of assessment could enhance the current clinical paradigm of proarrhythmic assessment of drugs. Specifically, such integrated assessment may be able to differentiate between selective hERG potassium channel blocking drugs that prolong QTc and have high torsade risk (e.g. dofetilide) from multichannel blocking drugs that also prolong QTc but have minimal risk for torsade (e.g. ranolazine). In addition, sex-specific analysis suggests that higher torsade risk in women is not because women are more sensitive to drug-induced QTc prolongation. Future strategies to use the ECG to detect multi-ion channel effects should use J-Tpeakc to detect the presence of late sodium current block.
