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. Gro...

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Bibliographic Details
Published in:Journal of clinical pharmacology 2011-06, Vol.51 (6), p.819-829
Main Authors: Lin, Yeong-Liang, Hsiao, Chia-Ling, Wu, Ya-Chi, Kung, Mei-Fen
Format: Article
Language:English
Subjects:
action potential duration
Action Potentials - drug effects
Animals
cutoff
Drug-Related Side Effects and Adverse Reactions - physiopathology
Ether-A-Go-Go Potassium Channels - antagonists & inhibitors
human ether-a-go-go-related gene
Humans
Inactivation, Metabolic - physiology
Long QT Syndrome - chemically induced
Long QT Syndrome - physiopathology
Models, Statistical
Potassium Channels, Voltage-Gated - antagonists & inhibitors
Risk Factors
ROC Curve
torsades de pointes
Torsades de Pointes - chemically induced
Torsades de Pointes - physiopathology
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Summary: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 Group 1 consisted of drugs that had been withdrawn or suspended from the market because of unacceptable TdP risk or for which numerous reports of TdP had been published.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 (Ikr), had lower half‐maximal inhibitory concentration (IC50) values for inhibition of HERG/Ikr, 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/Ikr 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.
ISSN:0091-2700
1552-4604
DOI:10.1177/0091270010372521