Electrophysiologic, Pharmacokinetic, and Pharmacodynamic Values Indicating a Higher Risk of Torsades de Pointes

Torsades de pointes (TdP) is a major safety concern with drugs that are submitted for regulatory approval. The study aimed to identify the electrophysiological, pharmacokinetic, and pharmacodynamic values indicating a higher risk of TdP. A number of QT-prolonging drugs were assigned to 2 groups. Group 1 consisted of drugs that had been withdrawn or suspended from the market because of unacceptable TdP risk or for which numerous reports of TdP had been published. Group 2 included drugs for which there had been isolated reports or no report. The results showed that drugs in group 1 induced greater inhibition of human ether-a-go-go-related gene (HERG) potassium current or the rapid component of the delayed rectifier potassium current (I(kr)), had lower half-maximal inhibitory concentration (IC₅₀) values for inhibition of HERG/I(kr), and induced greater QTc increases in humans. The cutoff values indicating a higher risk of TdP included an increase in action potential duration greater than 10% at concentration lower than 300 nM, inhibition of HERG/I(kr) greater than 30% at therapeutic concentration, IC₅₀ lower than 2 µM, a mean QTc increase greater than 15.5 milliseconds in monotherapy and 12.0 milliseconds with concurrent use of metabolic inhibitors, and an upper bound of its 95% confidence interval greater than 21 milliseconds in monotherapy and 19.4 milliseconds in the presence of metabolic inhibition.