Application of Trial Simulation in the Design of a Prospective Study for Concentration-QTc Analysis in Support of a Thor
- PDF / 1,656,723 Bytes
- 12 Pages / 595.276 x 790.866 pts Page_size
- 70 Downloads / 158 Views
Tutorial Application of Trial Simulation in the Design of a Prospective Study for Concentration-QTc Analysis in Support of a Thorough QT Study Waiver Peijuan Zhu,1,5 Chyi-Hung Hsu,1 Chuanpu Hu,2 Peggy Wong,3 Sherwin K. B. Sy,4 Partha Nandy,1 and Honghui Zhou2
Received 1 April 2020; accepted 16 July 2020
The concentration-QTc (C-QTc) analysis is often applied in the first-in-human (FIH) study to demonstrate the absence of a QTc effect in support of a TQT waiver. However, a C-QTc analysis without properly designed sensitivity could fail to conclude the absence of a QTc effect at high concentrations, even though the compound is QTc negative. This is because the 90% confidence interval (CI) of the model-derived ΔΔQTc grows wider with increasing concentration, and the upper-bound could cross the 10-ms threshold, even though the slope is close to 0. So far, there is no simple math formula to calculate the sensitivity/specificity of a C-QTc analysis. A PK/QTc trial simulation scheme was applied to optimize the design features of a C-QTc trial in FIH studies by evaluating the study’s sensitivity over a wide concentration range, circumventing the problem of not knowing the target concentration during FIH studies. It was also used to ensure that the specificity of the trial was well-controlled. Simulation showed that the study sensitivity can be quantitatively gauged by optimizing the dose range, the number of samples per subjects or subject number, and by sampling around Tmax, and at steady-state. The specificity of the trial can also be evaluated with this approach, and it is important to combine model-derived ΔΔQTc and slope estimate in the evaluation. The trial simulation approach helps maximize the probability of success of C-QTc analyses in FIH studies intended to support a TQT waiver. Abstract.
KEY WORDS: Concentration-QTc (C-QTc) analysis; Probability of success; Study design optimization; Thorough QT waiver; Trial simulation.
INTRODUCTION The revised International Council for Harmonization (ICH) E14 Questions and Answers document dated December 2015 introduced the possibility of using concentrationQTc (C-QTc) modeling as the primary analysis for assessing the QTc interval prolongation risk of new compounds (1). The C-QTc modeling approach can assess QTc prolongation using smaller than usual thorough QT (TQT) trials or phase I single ascending dose (SAD) or multiple ascending dose (MAD) studies because it harnesses the power of mixedeffect models to summarize data from all doses and
1
Clinical Pharmacology & Pharmacometrics, Janssen Research & Development LLC, Raritan, New Jersey, USA. 2 Clinical Pharmacology & Pharmacometrics, Janssen Research & Development LLC, Spring House, Pennsylvania, USA. 3 Quantitative Science, Janssen Research & Development LLC, Raritan, New Jersey, USA. 4 Department of Statistics, State University of Maringá, Maringá, Paraná, Brazil. 5 To whom correspondence should be addressed. (e–mail: [email protected])
timepoints and also characterizes QTc over the observed range of concentrations. It
Data Loading...
