TY - JOUR
T1 - Assessing the proarrhythmic potential of drugs
T2 - current status of models and surrogate parameters of torsades de pointes arrhythmias
AU - Thomsen, Morten Bækgaard
AU - Matz, Jørgen
AU - Volders, Paul G A
AU - Vos, Marc A
PY - 2006/10
Y1 - 2006/10
N2 - Torsades de pointes (TdP) is a potentially lethal cardiac arrhythmia that can occur as an unwanted adverse effect of various pharmacological therapies. Before a drug is approved for marketing, its effects on cardiac repolarisation are examined clinically and experimentally. This paper expresses the opinion that effects on repolarisation duration cannot directly be translated to risk of proarrhythmia. Current safety assessments of drugs only involve repolarisation assays, however the proarrhythmic profile can only be determined in the predisposed model. The availability of these proarrhythmic animal models is emphasised in the present paper. It is feasible for the pharmaceutical industry to establish one or more of these proarrhythmic animal models and large benefits are potentially available if pharmaceutical industries and patient-care authorities embraced these models. Furthermore, suggested surrogate parameters possessing predictive power of TdP arrhythmia are reviewed. As these parameters are not developed to finalisation, any meaningful study of the proarrhythmic potential of a new drug will include evaluation in an integrated model of TdP arrhythmia.
AB - Torsades de pointes (TdP) is a potentially lethal cardiac arrhythmia that can occur as an unwanted adverse effect of various pharmacological therapies. Before a drug is approved for marketing, its effects on cardiac repolarisation are examined clinically and experimentally. This paper expresses the opinion that effects on repolarisation duration cannot directly be translated to risk of proarrhythmia. Current safety assessments of drugs only involve repolarisation assays, however the proarrhythmic profile can only be determined in the predisposed model. The availability of these proarrhythmic animal models is emphasised in the present paper. It is feasible for the pharmaceutical industry to establish one or more of these proarrhythmic animal models and large benefits are potentially available if pharmaceutical industries and patient-care authorities embraced these models. Furthermore, suggested surrogate parameters possessing predictive power of TdP arrhythmia are reviewed. As these parameters are not developed to finalisation, any meaningful study of the proarrhythmic potential of a new drug will include evaluation in an integrated model of TdP arrhythmia.
KW - Animals
KW - Disease Models, Animal
KW - Humans
KW - Pharmaceutical Preparations
KW - Torsades de Pointes
U2 - 10.1016/j.pharmthera.2005.04.009
DO - 10.1016/j.pharmthera.2005.04.009
M3 - Journal article
C2 - 16714061
SN - 0163-7258
VL - 112
SP - 150
EP - 170
JO - Pharmacology & Therapeutics
JF - Pharmacology & Therapeutics
IS - 1
ER -