title: The role of concentration-effect relationships in the assessment of QTc interval prolongation.
abstract: Population pharmacokinetic and pharmacokinetic-pharmacodynamic (PKPD) modelling has been widely used in clinical research. Yet, its application in the evaluation of cardiovascular safety remains limited, particularly in the evaluation of pro-arrhythmic effects. Here we discuss the advantages of disadvantages of population PKPD modelling and simulation, a paradigm built around the knowledge of the concentration-effect relationship as the basis for decision making in drug development and its utility as a guide to drug safety. A wide-ranging review of the literature was performed on the experimental protocols currently used to characterize the potential for QT interval prolongation, both pre-clinically and clinically. Focus was given to the role of modelling and simulation for design optimization and subsequent analysis and interpretation of the data, discriminating drug from system specific properties. Cardiovascular safety remains one of the major sources of attrition in drug development with stringent regulatory requirements. However, despite the myriad of tests, data are not integrated systematically to ensure accurate translation of the observed drug effects in clinically relevant conditions. The thorough QT study addresses a critical regulatory question but does not necessarily reflect knowledge of the underlying pharmacology and has limitations in its ability to address fundamental clinical questions. It is also prone to issues of multiplicity. Population approaches offer a paradigm for the evaluation of drug safety built around the knowledge of the concentration-effect relationship. It enables quantitative assessment of the probability of QTc interval prolongation in patients, providing better guidance to regulatory labelling and understanding of benefit/risk in specific populations.
authors.affiliation: Medicines Discovery and Development, GlaxoSmithKline, Uxbridge, UK.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: France
authors.forename: Oscar
authors.initials: O
authors.lastname: Della Pasqua
mesh_terms: D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000175:diagnosis*; D008954:Models, Biological
keywords: ICH E14; PKPD modelling; QTc interval prolongation; cardiovascular safety; clinical trial simulations; drug development