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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

Abstract

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.

Abbreviations

AIC:

Akaike information criteria

C:

Concentration

CI:

Confidence intervals

Cmax :

Maximum concentration

C-QTc:

Concentration-QTc

ΔHR:

Baseline-corrected heart rate

ΔQTc:

Baseline-corrected QTc interval

ΔΔQTc:

ΔQTc interval corrected for placebo

ECG:

Electrocardiogram

Emax :

Maximum effect

ER:

Extended release

GOF:

Goodness-of-fit

hERG:

Human ether-a-go-go-related gene

HR:

Heart rate

ICH:

International Council for Harmonization

IR:

Immediate-release

ms:

Milliseconds

LME:

Linear mixed effects

MAD:

Multiple-ascending dose

MAP:

Modeling analysis plan

MD:

Multiple dose

PK:

Pharmacokinetic

PD:

Pharmacodynamics

QT:

QT interval on ECG

QTc:

QT interval corrected for heart rate

QTcF:

Fridericia corrected QT interval

SAD:

Single-ascending dose

SD:

Single dose

TQT:

Thorough QT/QTc

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Disclaimer

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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Correspondence to Christine Garnett.

Additional information

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). https://doi.org/10.1007/s10928-017-9558-5

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Keywords

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