DRUG-INDUCED TORSADE-DE-POINTES - PRECLIN ICAL AND CLINICAL-STUDIES FOR THE PREDICTION OF A POTENTIAL PROARRHYTHMIC ADVERSE DRUG REACTION

The risk of drug-induced torsade de pointes, a potentially lethal vent ricular arrhythmia, raises the problem of the early detection of the e ffects of any new chemical entity (NCE) on Ventricular repolarization since prolongation of myocardial repolarization isa major trigger amon g others (hypokalaemia, bradycardia, congenital abnormalities in cellu lar ionic channels) for this arrhythmia. During pre-clinical studies, the effects of a range of concentrations (10(-9) M to 10(-4) M) of NCE on the duration of the action potential of Purkinje and left ventricu lar myocardial cells (guinea-pig and rabbit) have to be measured. If t hese effects are present, the duration of QT interval on ECG recorded in animal studies (dogs) has to be carefully measured and correlated w ith plasma concentrations of NCE and/or its metabolite(s). During clin ical trials, additional studies have to be performed in order to docum ent QT interval-plasma concentration relationships and the influence o f heart rate on QT interval duration. Ambulatory ECG recordings will a ttest to the safety of the NCE and precautions for use of the drug wil l be established according to our knowledge of predisposing factors fo r a proarrhythmic effect. Should there be a notification of a case of torsade de points after a new drug has been launched, urgent consultat ions with the drug file will be necessary in order to assess which pre -clinical and clinical studies may be needed for a better evaluation o f the benefit/risk ratio of the new drug.