| Running thorough QT/QTc studies can be prevented by oncology drug toxicity. William Wheeler, at Spacelabs, considers solutions to this complex drug development problem
Although the definitive description of Torsade de Pointes (TdP) did not exist until 1966, quinidine syncope – a manifestation of TdP – was first described in 1905. However, the first documented oncology patient to die from therapy may possibly have occurred in 1821. The patient was treated with several medications that prolonged the QT interval, as well as purgatives that induced electrolyte abnormalities. That patient was Napoleon Bonaparte and he was receiving arsenic, not to treat his possible gastric carcinoma, but as a poison. Regardless of the intent, it appears likely that Napoleon may have died from TdP due to the interaction of arsenic with other compounds and factors such as electrolyte abnormalities. This so-called ‘perfect storm’ scenario is often seen in drug-induced TdP.
TdP is a rapid, highly variable, ventricular tachycardia named after the characteristic ECG changes described as a ‘twisting of the points’. Though TdP episodes are of variable length and can be asymptomatic or minimally symptomatic, they can frequently result in sudden death. TdP was an exoteric, congenital rhythm disturbance until the 1980s when an increasing number of drug-related TdP events were recognised. TdP and QT prolongation are the most common reason for withdrawal of marketed drugs or restrictions in their labelling. Although these types of effects upon the heart might be expected from cardiovascular drugs, it was the unexpected occurrence in non-cardiovascular compounds that has prompted the current interest in TdP.
Regulatory interest in the proarrhythmic potential for noncardiovascular compounds in development has culminated in the ICH document E14-Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non- Antiarrhythmic Drugs, released in October, 2005. The document contains general guidance for the performance of a ‘thorough QT/QTc’ study (TQTS) in healthy volunteers, utilising therapeutic and supraphysiologic doses with both placebo and active controls. The outcome of such a trial can be critical to the viability of a drug because a ‘positive’ study can result in a much more expensive late stage development programme and potentially a significant safety issue for compounds indicated for non-life-threatening diseases. In this article we will discuss various approaches to obtaining adequate QT data when a TQTS can not be performed.
DRUG-INDUCED LQTS
Terfenadine was viewed as a major advance in the treatment of seasonal allergies because of its non-sedating qualities and quickly became a market leader. In the 1980s, occasional cases of TdP and sudden death were described in patients taking overdoses of the drug, but in 1990 the first case of TdP was described in patients taking therapeutic doses. Typically these patients were taking other medications that either had additive effects upon the QT interval or modified the metabolism of terfenadine. By 1992 the sponsor had accumulated 15 sudden deaths considered due to TdP and 83 cases of TdP. It was over four years later, in January 1997, that the FDA recommended withdrawal of the compound from the US market. |
