Other Agents Of The Same Pharmacological Class

This particular scenario requires that the safety database be expanded to exclude any class-related risks. A number of antianginal drugs have been shown to prolong the QT interval and induce proarrhythmias. These include prenylamine, be-pridil, lidoflazine, tedisamil, perhexiline, fendiline and aprindine. Therefore, terodiline as well as other antianginal drugs should be evaluated routinely during their preclinical and clinical development for their potential to prolong the QT interval just as all non-steroidal anti-inflammatory drugs (NSAIDs) are evaluated for gastrointestinal toxicity.

As it was, the clinical trials database on terodi-line was comparable with those for other drugs intended for urinary incontinence. In retrospect, however, it was not large enough for a drug with its chemical and antianginal pedigree. It had included 8 controlled (n = 229) and 6 uncontrolled (n = 147) studies with a total patient population of 376 exposed to terodiline. Of these, 241 had received the drug for up to 1 month and a further 39 for 2-3 months. Seventy-five patients had been treated for 4-12 months.

Following structural modifications of a lead compound, drugs are often discovered to have more potent activity at pharmacological targets other than originally intended. Therefore, drugs cross "therapeutic boundaries". A number of important QT-prolonging drugs belong to a specific chemical class usually associated with one therapeutic area but have later been developed or used clinically in an entirely different therapeutic area. Terfenadine is another typical example. It was discovered through a central nervous system programme aimed at synthesising new neuroleptic agents but because of its potent secondary pharmacological effects at the ^-antihistamine receptor, it was developed as the first non-sedating ^-antihistamine. It was a highly successful and popular drug until withdrawn due to reports of torsade de pointes resulting from drug interactions. Like all neuroleptics, it attracted considerable regulatory attention because of its effect on the QT interval. Sildenafil, originally intended for development as an antianginal drug, was developed instead for male erectile dysfunction and it is not surprising that at high concentrations, it has been shown to prolong cardiac repolarisation by blocking the rapid component of the delayed rectifier potassium current (Geelen et al., 2000). At clinical doses, a significant effect on QT interval is most unlikely (Sofowora et al., 2001), especially since the drug is used intermittently.


When the risk of QT interval prolongation is high, signals are often present in the clinical trials database. Pimozide, for example, was found to prolong the QT interval in about 10% of the patients in one study in 1989. Similarly, halofan-trine was also found during early clinical trials to produce an effect on the QT interval.

As a result of experiences with some of the established as well as newly introduced drugs, clinical trials programmes now usually include electrocardiographic monitoring in at least one or two large studies, particularly those investigating high doses or use of metabolic inhibitors. Depending on the findings from these "exploratory'' studies, the database may require expansion to address the risk more fully.

In view of the many high profile drugs, which had attracted considerable regulatory attention in the years 1990-1996 due to their potential to prolong the QT interval and induce torsades de pointes, the CPMP adopted two significant documents in December 1997.

One of these was the CPMP document "Points to Consider: The Assessment of the Potential for QT Interval Prolongation by Non-cardiovascular Medicinal Products'' (Anon, 1997a). The recommendations contained within this document are not mandatory but they do represent a strategy by which EU regulators would like to see an NCE investigated for its potential to induce proarrhyth-mic prolongation of the QT interval.

Following the regulatory concerns and the CPMP document, the European Society of Cardiology (ESC) organised a Policy Conference on drug-induced QT interval prolongation under the auspices of the ESC Committee for Scientific and Clinical Initiatives. A Report from this conference has now been published, endorsing a more rigorous investigation of the preclinical electro-physiological and clinical electrocardiographic effects of new drugs (Haverkamp et al., 2000).

The other significant document was the CPMP "Note for Guidance on the Investigation of Drug Interactions" (Anon, 1997b). A number of drugs such as terfenadine, astemizole, pimozide, and cisapride have the propensity to induce torsade de pointes and other proarrhythmias as a result of drug interactions.

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