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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

Ferber, Georg, Wang, Duolao ORCID: https://orcid.org/0000-0003-2788-2464 and Täubel, Jörg (2014) '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'. The Journal of Clinical Pharmacology, Vol 54, Issue 12, pp. 1400-1406.

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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.

Item Type: Article
Subjects: QU Biochemistry > QU 26.5 Informatics. Automatic data processing. Computers
QV Pharmacology > QV 38 Drug action.
QV Pharmacology > QV 4 General works
Faculty: Department: Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI): https://doi.org/10.1002/jcph.347
Depositing User: Lynn Roberts-Maloney
Date Deposited: 11 May 2015 09:13
Last Modified: 06 Feb 2018 13:09
URI: http://archive.lstmed.ac.uk/id/eprint/5132

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