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Scientific white paper on concentration-QTc modeling

An Author Correction to this article was published on 12 January 2018

This article has been updated


The International Council for Harmonisation revised the E14 guideline through the questions and answers process to allow concentration-QTc (C-QTc) modeling to be used as the primary analysis for assessing the QTc interval prolongation risk of new drugs. A well-designed and conducted QTc assessment based on C-QTc modeling in early phase 1 studies can be an alternative approach to a thorough QT study for some drugs to reliably exclude clinically relevant QTc effects. This white paper provides recommendations on how to plan and conduct a definitive QTc assessment of a drug using C-QTc modeling in early phase clinical pharmacology and thorough QT studies. Topics included are: important study design features in a phase 1 study; modeling objectives and approach; exploratory plots; the pre-specified linear mixed effects model; general principles for model development and evaluation; and expectations for modeling analysis plans and reports. The recommendations are based on current best modeling practices, scientific literature and personal experiences of the authors. These recommendations are expected to evolve as their implementation during drug development provides additional data and with advances in analytical methodology.

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Change history

  • 12 January 2018

    The original version of this article unfortunately contained an error in Equation 1 under the section “Pre-specified linear mixed effects model”. The correct equation has given below.



Akaike information criteria




Confidence intervals

Cmax :

Maximum concentration




Baseline-corrected heart rate


Baseline-corrected QTc interval


ΔQTc interval corrected for placebo



Emax :

Maximum effect


Extended release




Human ether-a-go-go-related gene


Heart rate


International Council for Harmonization






Linear mixed effects


Multiple-ascending dose


Modeling analysis plan


Multiple dose






QT interval on ECG


QT interval corrected for heart rate


Fridericia corrected QT interval


Single-ascending dose


Single dose


Thorough QT/QTc


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The views presented in this article are the personal opinions of the authors and do not reflect the official views of their respective organizations.

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Corresponding author

Correspondence to Christine Garnett.

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The original version of this article was revised: The error in Equation 1 has been corrected.

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Garnett, C., Bonate, P.L., Dang, Q. et al. Scientific white paper on concentration-QTc modeling. J Pharmacokinet Pharmacodyn 45, 383–397 (2018).

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  • Concentration-QTc model
  • ICH E14
  • Thorough QT (TQT) study
  • Pharmacokinetics/pharmacodynamics