title: Drug-induced QT interval prolongation: does ethnicity of the thorough QT study population matter?
abstract: Inter-ethnic differences in drug responses have been well documented. Drug-induced QT interval prolongation is a major safety concern and therefore, regulatory authorities recommend a clinical thorough QT study (TQT) to investigate new drugs for their QT-prolonging potential. A positive study, determined by breach of a preset regulatory threshold, significantly influences late phase clinical trials by requiring intense ECG monitoring. A few studies that are currently available, although not statistically conclusive at present, question the assumption that ethnicity of the study population may not influence the outcome of a TQT study. Collective consideration of available pharmacogenetic and clinical information suggests that there may be inter-ethnic differences in QT-prolonging effects of drugs and that Caucasians may be more sensitive than other populations. The information also suggest s that (a) these differences may depend on the QT-prolonging potency of the drug and (b) exposure-response (E-R) analysis may be more sensitive than simple changes in QT(c) interval in unmasking this difference. If the QT response in Caucasians is generally found to be more intense than in non-Caucasians, there may be significant regulatory implications for domestic acceptance of data from a TQT study conducted in foreign populations. However, each drug will warrant an individual consideration when extrapolating the results of a TQT study from one ethnic population to another and the ultimate clinical relevance of any difference. Further adequately designed and powered studies, investigating the pharmacologic properties and E-R relationships of additional drugs with different potencies, are needed in Caucasians, Oriental/Asian and African populations before firm conclusions can be drawn.
authors.affiliation: Rashmi Shah Consultancy Ltd, Gerrards Cross, UK. clinical.safety@hotmail.co.uk
authors.forename: Rashmi R
authors.initials: RR
authors.lastname: Shah
mesh_terms: D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D005006:Ethnicity; D006801:Humans; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000208:ethnology*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D010597:Pharmacogenetics; D044469:Racial Groups / Q000235:genetics; D035842:Research Subjects
chemical_list: D004364:Pharmaceutical Preparations