Joanne Zhang1, Huifang Chen1, Yi Tsong1, Norman Stockbridge2. 1. 1 Division of Biometrics VI, Office of Biostatistics, Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA. 2. 2 Division of Cardiovascular and Renal Products, Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
Abstract
BACKGROUND: The coherence between the relationship of QTc and drug plasma concentration (this relationship is measured through the slope) and ICH E14 findings based on hundreds of QT study reports was studied. RESULTS: Based on ICH E14 analysis, our findings indicate that if the slope was not positive, in most cases (86%) the corresponding QT studies were also negative. If the slope was positive, 92% of the corresponding QT studies were also positive. CONCLUSIONS: In exploring whether a thorough QT (TQT) study may be needed, we recommend that the relationship analysis between QTc and drug plasma concentration be performed when proper single ascending dose (SAD) and multiple ascending dose (MAD) studies are available. If the relationship cannot be detected and the 90% upper confidence interval at a fixed concentration level (50th or 75th percentile, or mean peak plasma concentration [Cmax]) is below a certain threshold level (eg, 10 milliseconds), then a TQT study might be unnecessary. If the relationship can be established and the 90% lower confidence interval at a fixed concentration level (eg, mean Cmax) is greater than 10 milliseconds, further investigation is needed. If the signal is real, one might choose intensive safety monitoring during later drug development instead of a TQT study for a good compound. However, there are still some gray areas in which this analysis alone cannot determine the potential QT liability of the drug, and a TQT type of study might be worth considering.
BACKGROUND: The coherence between the relationship of QTc and drug plasma concentration (this relationship is measured through the slope) and ICH E14 findings based on hundreds of QT study reports was studied. RESULTS: Based on ICH E14 analysis, our findings indicate that if the slope was not positive, in most cases (86%) the corresponding QT studies were also negative. If the slope was positive, 92% of the corresponding QT studies were also positive. CONCLUSIONS: In exploring whether a thorough QT (TQT) study may be needed, we recommend that the relationship analysis between QTc and drug plasma concentration be performed when proper single ascending dose (SAD) and multiple ascending dose (MAD) studies are available. If the relationship cannot be detected and the 90% upper confidence interval at a fixed concentration level (50th or 75th percentile, or mean peak plasma concentration [Cmax]) is below a certain threshold level (eg, 10 milliseconds), then a TQT study might be unnecessary. If the relationship can be established and the 90% lower confidence interval at a fixed concentration level (eg, mean Cmax) is greater than 10 milliseconds, further investigation is needed. If the signal is real, one might choose intensive safety monitoring during later drug development instead of a TQT study for a good compound. However, there are still some gray areas in which this analysis alone cannot determine the potential QT liability of the drug, and a TQT type of study might be worth considering.
Entities:
Keywords:
QTc; coherence; drug plasma concentration; relationship; sensitivity; specificity
Authors: Andreas Becker; Emily C Martin; David Y Mitchell; Roland Grenningloh; Andrew T Bender; Julien Laurent; Harald Mackenzie; Andreas Johne Journal: Clin Transl Sci Date: 2019-11-29 Impact factor: 4.689