Is it Safe? Adverse drug effects and cardiac arrhythmias

Abstract

The potentially life-threatening polymorphic ventricular arrhythmia Torsade de Pointes (TdP) generally occurs in the setting of delayed ventricular repolarization, as reflected on the ECG by a prolonged QT interval. A growing number of drugs are associated with QT prolongation and/or TdP, as a result, development of promising new drugs has been aborted, and already marketed drugs have received severe restrictions or have been withdrawn. To address this cardiac safety issue, international guidelines have been implemented. For non-clinical testing, an IKr assay and a QT assay are recommended. The IKr assay evaluates the effect of a drug on the IKr current in single cells or multicellular preparations ranging from cell clusters to whole hearts. The effect of the drug on the QT interval is determined in healthy animals. The clinical evaluation, the ‘thorough QT/ QTC study’ carried out in healthy volunteers, is critical for current decision-making. If QTC prolongation is ≤5 ms a drug is safe, a QTC prolongation of >20 ms is deemed unsafe. Additional verification is needed if QTC prolongation falls in between. This thesis is mainly focused on cardiac safety pharmacology and several weaknesses of the current approach were addressed. The use of an alternative surrogate parameter for drug-induced TdP, beat-to-beat variability of repolarization (BVR) quantified as short-term variability (STV) is reviewed, and was found to be more predictive than the QT interval. Also in antiarrhythmic drug efficacy testing, STV seemed to perform better. In addition, its usefulness in determining individuals at risk was explored. Furthermore, evidence is provided that the antiarrhythmic drug vernakalant does not induce TdP arrhythmias in our cAVB dog model despite considerable QT prolongation. Several model systems are used in safety testing, but proarrhythmic models, which would circumvent the use of QT interval and instead provide a direct arrhythmic endpoint, are not yet recommended. We have compared five frequently used in-vitro and in-vivo proarrhythmic model systems. While isolated cardiomyocytes from remodeled and unremodeled hearts lack specificity, the whole animal models and the stem cell clusters yielded satisfactory results. In order to increase the reliability and usefulness of the methoxamine-sensitized rabbit model, the effect of 3 anesthetic protocols was evaluated. Anesthesia severely influenced TdP induction by dofetilide, while conduction disturbances remained present. In contrast, dofetilide did not induce TdP in healthy rabbits, which again emphasizes the use of sensitized proarrhythmic (animal) models. Chronic drug effects pose a potential arrhythmic threat but are not considered in the current guidelines. To study these drug effects, the antiprotozoal agent pentamidine was used to study protein trafficking and degradation. Pentamidine increased the degradation of Kir2.1 and this effect could be corrected by inhibiting different steps in the normal degradation route. Furthermore, pentamidine inhibits proper transport of the hERG protein to its destination on the surface of the cell. Also this could be corrected, application of drugs that bind to the pore of the hERG ion channel restored proper transport in the presence of pentamidine.