Development of QTc prolongation model incorporating circadian rhythm using harmonic model

Abstract

1. QT prolongation is one of the major safety tests used in the development of a new drug. The ICH guidelines for the evaluation of QT prolongation recommend the use of the in vitro hERG assay and the in vivo telemetry test. However, QT intervals change under normal conditions due to circadian rhythm and can affect the results of the tests. In this study, we developed a PK/PD model to describe the QT interval after the administration of astemizole allowing for the normal changes by circadian rhythm.

2. The typical PK parameters of absorption rate constant (k_a), volume of distribution (V_c and V_m), metabolism (k_m), and elimination rate constant (k_el and k_el-m) were 0.49 h⁻¹, 4950 L, 20 L, 0.0127 h⁻¹, 0.0095 h⁻¹, and 0.95 h⁻¹, respectively. The final PK/PD model was the biophase model with the modified harmonic model. The typical PK/PD parameters, base QTc interval (QT₀), amplitude (T₁, T₃), period of QTc interval changing (T₂, T₄), and EC₅₀ were 233 ms, 3.31, 1.5, −9.24 h, 1.85 h, and 0.81 ng/ml, respectively.

3. The PK/PD model to explain the changes of the QT interval that allows normal changes in the circadian rhythm after the administration of astemizole was developed successfully. This final model can be applied to the development of a human model.

• Astemizole
• circadian rhythm
• NONMEM
• PK/PD modeling
• QT prolongation

Declaration of interest

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (Grant 2009-0093815). This work was supported by research fund of Chungnam National University. The authors declare no conflict of interest.