title: Concentration-effect modeling based on change from baseline to assess the prolonging effect of drugs on QTc together with an estimate of the circadian time course.
abstract: As ICH E14 was adopted by the US FDA and the EU CPMC in 2005, thorough QT studies have routinely been analyzed by looking at the time-matched difference between (baseline corrected) QTcF or QTcI under the supra-therapeutic dose and placebo. A study is considered negative, if the two-sided 90% confidence interval for this difference is below 10 ms for all investigated time points. ICH E14 suggests including a positive control, such as moxifloxacin, for assay sensitivity. Concentration-response analysis has been considered a more powerful alternative, but its application to parallel group studies was hampered as a double difference of QTcF per subject cannot be calculated. Recently, a new model based on change from baseline with fixed time and concentration effects has been proposed. It allows for a placebo-corrected prediction of the drug effect with an unbiased standard error, and the estimate of a time effect can be used for assay sensitivity. We demonstrate this approach, utilizing 2 studies reported elsewhere with a crossover design. We compare the results from a conventional concentration-response analysis based on the difference to placebo with results from the novel analysis based on the change from average baseline that includes a fixed time effect.
authors.affiliation: Statistik Georg Ferber GmbH, Cagliostrostrasse 14, Riehen, Switzerland.
authors.forename: Georg
authors.initials: G
authors.lastname: Ferber
authors.forename: Duolao
authors.initials: D
authors.lastname: Wang
authors.forename: Jörg
authors.initials: J
authors.lastname: Täubel
mesh_terms: D000700:Analgesics / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D024841:Fluoroquinolones / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D018565:Food-Drug Interactions; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000378:metabolism*; D008954:Models, Biological; D009025:Morpholines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000077266:Moxifloxacin; D011720:Pyrazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C576663:4-(2-((5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl)oxy)ethyl)morpholine; D000700:Analgesics; D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D009025:Morpholines; D011720:Pyrazoles; D000077266:Moxifloxacin
keywords: QTc; assay sensitivity; concentration-response model; moxifloxacin; thorough QT study