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J Pharmacokinet Pharmacodyn. 2018 Jun;45(3):383-397. doi: 10.1007/s10928-017-9558-5. Epub 2017 Dec 5.

Scientific white paper on concentration-QTc modeling.

Author information

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@fda.hhs.gov.
2
Astellas Pharma Global Development, Northbrook, IL, USA.
3
Office of Biostatistics, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
4
Statistik Georg Ferber GmbH, Riehen, Switzerland.
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.
6
Biostatistics, Merck & Co., Inc., Gwynedd, PA, USA.
7
Clinical Pharmacology, Pfizer Inc., New York, NY, USA.
8
Stanford University, Stanford, CA, USA.
9
Clinical Reporting, Novo Nordisk A/S, Bagsværd, Denmark.

Erratum in

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.

KEYWORDS:

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

PMID:
29209907
DOI:
10.1007/s10928-017-9558-5

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