title: Electrophysiologic, pharmacokinetic, and pharmacodynamic values indicating a higher risk of torsades de pointes.
abstract: 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 Group 1 consisted of drugs that had been withdrawn or suspended from the market because of unacceptable TdP risk or for which numerous reports of TdP had been published.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.
authors.affiliation: Center for Drug Evaluation, 1F, No 15-1, Section 1, Hangjou S Road, Taipei, Taiwan 100. yllin@cde.org.tw
authors.forename: Yeong-Liang
authors.initials: YL
authors.lastname: Lin
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Hsiao
authors.forename: Ya-Chi
authors.initials: YC
authors.lastname: Wu
authors.forename: Mei-Fen
authors.initials: MF
authors.lastname: Kung
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D064420:Drug-Related Side Effects and Adverse Reactions / Q000503:physiopathology*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D008658:Inactivation, Metabolic / Q000502:physiology*; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D015233:Models, Statistical; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors; D012372:ROC Curve; D012307:Risk Factors; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology*
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D024642:Potassium Channels, Voltage-Gated