title: Operational Characteristics of Linear Concentration-QT Models for Assessing QTc Interval in the Thorough QT and Phase I Clinical Studies.
abstract: Concentration-QTc (C-QTc) analysis can be used as an alternative to the standard statistical methods in clinical QT studies. Pharmacokinetic/pharmacodynamics (PK/PD) simulations were performed to assess the operating characteristics of four C-QTc models. False negatives were 2-6% for crossover and 2-9% for parallel studies, with 12 to 60 subjects per treatment for a dose with 10-ms mean effect. All C-QTc models tested gave less than +1 ms mean bias in the ΔΔQTcmax prediction. The power to exclude 10 ms was >80% across all study designs and sizes, for a dose with 3-ms mean effect. The study demonstrates that linear C-QTc models have adequate sensitivity and specificity when the simulation and data analytical models are the same. C-QTc models that incorporate time- and treatment-specific terms give the least biased ΔΔQTcmax predictions under scenarios of model-misspecifications and offer an advantage when applying to real clinical data where the underlying relationship is not known.
authors.affiliation: Division of Cardiovascular and Renal Products, Office of New Drugs, Center for Drug Evaluation and Research, FDA, Silver Spring, Maryland, USA.
authors.forename: C
authors.initials: C
authors.lastname: Garnett
authors.affiliation: Office of the Commissioner, FDA, Silver Spring, Maryland, USA.
authors.forename: K
authors.initials: K
authors.lastname: Needleman
authors.affiliation: Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation and Research, FDA, Silver Spring, Maryland, USA.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: University of Minnesota, College of Pharmacy, Department of Experimental and Clinical Pharmacology, Minneapolis, Minnesota, USA.
authors.forename: R
authors.initials: R
authors.lastname: Brundage
authors.affiliation: Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation and Research, FDA, Silver Spring, Maryland, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
mesh_terms: D017321:Clinical Trials, Phase I as Topic / Q000379:methods; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000379:methods*; D005188:False Negative Reactions; D006801:Humans; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D012107:Research Design; D012680:Sensitivity and Specificity
chemical_list: D004364:Pharmaceutical Preparations