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

VL - 112

SP - 150

EP - 170

JO - Pharmacology and Therapeutics, Part A: Chemotherapy, Toxicology and

JF - Pharmacology and Therapeutics, Part A: Chemotherapy, Toxicology and

SN - 0163-7258

IS - 1

ER -