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Scientific white paper on concentration-QTc modeling

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

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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.

Author information

Authors and Affiliations

  1. Division of Cardiovascular and Renal Products, Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA

    Christine Garnett

  2. Astellas Pharma Global Development, Northbrook, IL, USA

    Peter L. Bonate

  3. Statistik Georg Ferber GmbH, Riehen, Switzerland

    Georg Ferber

  4. Office of Biostatistics, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA

    Qianyu Dang & Dalong Huang

  5. Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA

    Jiang Liu & Yaning Wang

  6. Biostatistics, Merck & Co., Inc., Gwynedd, PA, USA

    Devan Mehrotra

  7. Clinical Pharmacology, Pfizer Inc., New York, NY, USA

    Steve Riley

  8. Stanford University, Stanford, CA, USA

    Philip Sager

  9. Clinical Reporting, Novo Nordisk A/S, Bagsværd, Denmark

    Christoffer Tornoe

Authors
  1. Christine Garnett
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  2. Peter L. Bonate
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  3. Qianyu Dang
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  4. Georg Ferber
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  5. Dalong Huang
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  6. Jiang Liu
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  7. Devan Mehrotra
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  8. Steve Riley
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  9. Philip Sager
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  10. Christoffer Tornoe
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  11. Yaning Wang
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Corresponding author

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

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