title: Concentration-QT relationships play a key role in the evaluation of proarrhythmic risk during regulatory review.
abstract: The criterion for assessing whether a drug prolongs QT as described in the International Conference on Harmonization topic E14 guideline does not explicitly account for individual drug concentrations. The authors' experience with reviewing QT studies indicates that understanding the relationship, if any, between individual drug concentration and QT change provides important additional information to support regulatory decision making. Therefore, regulatory reviews of "thorough QT" studies routinely include a characterization of the concentration-QT relationship. The authors provide examples to illustrate how the concentration-QT relationship has been used to plan and interpret the thorough QT study, to evaluate QT risk for drugs that have no thorough QT studies, to assess QT risk in subpopulations, to make dose adjustments, and to write informative drug labels.
authors: Office of Clinical Pharmacology, Center of Drug Evaluation and Reseach, Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20903-0002, USA. christine.garnett@fda.hhs.gov
authors: Christine E
authors: CE
authors: Garnett
authors: Nhi
authors: N
authors: Beasley
authors: V Atul
authors: VA
authors: Bhattaram
authors: Pravin R
authors: PR
authors: Jadhav
authors: Rajanikanth
authors: R
authors: Madabushi
authors: Norman
authors: N
authors: Stockbridge
authors: Christoffer W
authors: CW
authors: Tornøe
authors: Yaning
authors: Y
authors: Wang
authors: Hao
authors: H
authors: Zhu
authors: Jogarao V
authors: JV
authors: Gobburu
mesh_terms: D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000175:diagnosis; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D015507:Drugs, Investigational / Q000009:adverse effects*; D017408:Guidelines as Topic; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000175:diagnosis; D018570:Risk Assessment / Q000379:methods; D012307:Risk Factors
chemical_list: D015507:Drugs, Investigational