title: Pharmacogenetic aspects of drug-induced torsade de pointes: potential tool for improving clinical drug development and prescribing.
abstract: Drug-induced torsade de pointes (TdP) has proved to be a significant iatro-genic cause of morbidity and mortality and a major reason for the withdrawal of a number of drugs from the market in recent times. Enzymes that metabolise many of these drugs and the potassium channels that are responsible for cardiac repolarisation display genetic polymorphisms. Anecdotal reports have suggested that in many cases of drug-induced TdP, there may be a concealed genetic defect of either these enzymes or the potassium channels, giving rise to either high plasma drug concentrations or diminished cardiac repolarisation reserve, respectively. The presence of either of these genetic defects may predispose a patient to TdP, a potentially fatal adverse reaction, even at therapeutic dosages of QT-prolonging drugs and in the absence of other risk factors. Advances in pharmacogenetics of drug metabolising enzymes and pharmacological targets, together with the prospects of rapid and inexpensive genotyping procedures, promise to individualise and improve the benefit/risk ratio of therapy with drugs that have the potential to cause TdP. The qualitative and the quantitative contributions of these genetic defects in clinical cases of TdP are unclear because not all of the patients with TdP are routinely genotyped and some relevant genetic mutations still remain to be discovered. There are regulatory guidelines that recommend strategies aimed at uncovering the risk of TdP associated with new chemical entities during their development. There are also a number of guidelines that recommend integrating pharmacogenetics in this process. This paper proposes a strategy for integrating pharmacogenetics into drug development programmes to optimise association studies correlating genetic traits and endpoints of clinical interest, namely failure of efficacy or development of repolarisation abnormalities. Until pharmacogenetics is carefully integrated into all phases of development of QT-prolonging drugs and large-scale studies are undertaken during their post-marketing use to determine the genetic components involved in induction of TdP, routine genotyping of patients remains unrealistic. Even without this pharmacogenetic data, the clinical risk of TdP can already be greatly minimised. Clinically, a substantial proportion of cases of TdP are due to the use of either high or usual dosages of drugs with potential to cause TdP in the presence of factors that inhibit drug metabolism. Therefore, choosing the lowest effective dose and identifying patients with these non-genetic risk factors are important means of minimising the risk of TdP. In view of the common secondary pharmacology shared by these drugs, a standard set of contraindications and warnings have evolved over the last decade. These include factors responsible for pharmacokinetic or pharmacodynamic drug interactions. Among the latter, the more important ones are bradycardia, electrolyte imbalance, cardiac disease and co-administration of two or more QT-prolonging drugs. In principle, if large scale prospective studies can demonstrate a substantial genetic component, pharmacogenetically driven prescribing ought to reduce the risk further. However, any potential benefits of pharmacogenetics will be squandered without any reduction in the clinical risk of TdP if physicians do not follow prescribing and monitoring recommendations.
authors.affiliation: Medicines and Healthcare products Regulatory Agency, London, United Kingdom. rashmi.shah@mhra.gsi.gov.uk
authors.forename: Rashmi R
authors.initials: RR
authors.lastname: Shah
mesh_terms: D002986:Clinical Trials as Topic; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D064420:Drug-Related Side Effects and Adverse Reactions; D005838:Genotype; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D015221:Potassium Channels / Q000235:genetics; D012307:Risk Factors; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000235:genetics* / Q000503:physiopathology
chemical_list: D015221:Potassium Channels; D019389:Cytochrome P-450 CYP2D6