Scientific white paper on concentration-QTc modeling

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.

Implications of Individual QT/RR Profiles—Part 1: Inaccuracies and Problems of Population-Specific QT/Heart Rate Corrections

“…Our results also need to be considered independent of the concentration–QTc interval analysis [9, 14]. While concentration–QTc interval analysis is a powerful tool in the assessment of drug-induced QTc interval changes, its successful application is based on the validity of the QTc interval values.…”

Thorough QT/QTc in a Dish: An In Vitro Human Model That Accurately Predicts Clinical Concentration‐QTc Relationships

“…The International Conference on Harmonization (ICH) E14 guideline for the TQT study states that the “threshold level of regulatory concern…is around 5 ms as evidenced by an upper bound of the 95% credible interval (CI) around the mean effect on QTc of 10 ms.” Overall, incorporation of these preclinical and clinical tests has been widely credited with the reduction in drugs with pro‐arrhythmic risk, but the high cost of the TQT study, estimated to be 1–4 million dollars, has led to efforts to develop both clinical and preclinical alternatives. For instance, both the ICH and the US Food and Drug Administration (FDA) now allow an alternative TQT study that involves concentration‐QTc (C‐QTc) modeling of QTc data collected in early phase I studies …”

“…We have previously shown that iPSC‐derived cardiomyocytes from a moderate‐sized sample of healthy subjects ( n = 27) are a highly reproducible in vitro population model . Notably, this sample size is greater than those recommended to control false negatives in C‐QTc modeling‐based TQT studies . We, therefore, hypothesized that the C‐QTc modeling of iPSC‐derived cardiomyocytes from a diverse sample of human subjects can serve as a “TQT study in a dish.” To test this hypothesis, we first investigate whether a population‐based in vitro model in combination with in silico pharmacodynamic (PD) modeling can predict the clinical C‐QTc relationship ( Figure a ).…”

Assessment of Azeliragon QTc Liability Through Integrated, Model‐Based Concentration QTc Analysis

“…This was followed by the ICH E14 Guideline: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non‐Antiarrhythmic Drugs Questions & Answers (R3) document (December 2015), which was used in the design of the present analysis. Since then, a white paper has proposed an easier approach to concentration‐QT analysis . This newer approach suggests the use of a more efficient method using data from the single‐ascending‐dose and repeat‐ascending‐dose studies only.…”