title: Delayed effects in the exposure-response analysis of clinical QTc trials.
abstract: In clinical development, thorough QT interval/corrected QT interval (QT/QTc) studies are performed to demonstrate that new investigational drugs do not change cardiac repolarization. In addition to the analysis recommended by ICH E14, exposure-response modeling has recently gained increased scientific attention. A direct concentration-QTc relationship is usually assumed with this pharmacokinetics (PK) QT analysis. Consequently, unconsidered effect delays might lead to severe bias in estimation. Although literature and the Food and Drug Administration (FDA) recommend checking for hysteresis, little guidance is given for evaluating the presence of lagged effects. Based on simulated delay scenarios, we derive a metric that allows for the detection of relevant effect delays. With this, the necessity for refined modeling of lag times can be easily recognized.
authors.affiliation: Clinical Biostatistics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. patricia.glomb@boehringer-ingelheim.com
authors.forename: Patricia
authors.initials: P
authors.lastname: Glomb
authors.forename: Arne
authors.initials: A
authors.lastname: Ring
mesh_terms: D000465:Algorithms; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data*; D003198:Computer Simulation / Q000706:statistics & numerical data; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D015507:Drugs, Investigational / Q000009:adverse effects / Q000032:analysis; D004562:Electrocardiography / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007391:International Cooperation; D016014:Linear Models; D008133:Long QT Syndrome / Q000150:complications / Q000188:drug therapy*; D013997:Time Factors; D016171:Torsades de Pointes / Q000209:etiology; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D015507:Drugs, Investigational