Early QT assessment--how can our confidence in the data be improved?

Abstract

Exposure-response (ER) analysis has emerged as an important tool to interpret QT data from thorough QT (TQT) studies and allows the prediction of effects in the targeted patient population. Recently, ER analysis has also been applied to data from early clinical pharmacology studies, such as single and multiple ascending dose studies, in which high plasma concentrations are often achieved. In line with this, there is an on-going discussion between sponsors, academicians and regulators on whether 'early QT assessment' can provide sufficiently high confidence in assessment of QT prolongation to replace the TQT study. In this article, we discuss how QT assessment can be applied to early clinical studies ('early QT assessment') and what we believe is needed to achieve the same high confidence in the data as we currently obtain from data from the TQT study. The power to exclude a QTc effect exceeding 10 ms in small sample sizes using ER analysis will be discussed and compared with time-matched analysis, as described in the ICH E14 guidance. Two examples of early QT assessment are shared; one negative and one positive, and the challenge in terms of demonstrating assay sensitivity in the absence of a pharmacological positive control will be discussed. Finally, we describe a recent research proposal, which may generate data to support the replacement of the TQT study with data from QT assessment in early phase 1 studies.

Keywords: Early QT assessment; PK/PD thorough QT study; QT; QT/QTc; healthy volunteers.

Figure 1

The model based estimate (solid black line) with 90% CI (grey shaded area) is shown across the range of plasma concentrations observed in the SAD study. The horizontal red line shows the plasma concentration divided into deciles and the vertical, red bars show the observed ΔΔQT_cF with 90% CI within each plasma concentration decile (plotted at the median concentration of each decile). As shown by the upper bound of the 90% CI, a drug-induced effect on the QT_c interval exceeding 10 ms could be excluded at all observed plasma concentrations. , median concentration quantiles; , mean (90% CI) predicted QT_cF prolongation

Figure 2

A emonstrated with an increase of approximately 1.85 ms (90% CI ± 0.45) per 100 ng ml⁻¹ increase in plasma concentration. At plasma concentrations around 1 μg ml⁻¹, the predicted QT_c effect is around 18 ms with an upper bound of the CI of 23 ms. , observed QT_cF (mean ± 90% CI); , model predicted effect on QT_cF (mean ± 90% CI)