title: 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 (ka), volume of distribution (Vc and Vm), metabolism (km), and elimination rate constant (kel and kel-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.
authors.affiliation: College of Pharmacy, Chungnam National University , Daejeon , Korea and.
authors.forename: Hyun-moon
authors.initials: HM
authors.lastname: Back
authors.forename: Jong-Hwa
authors.initials: JH
authors.lastname: Lee
authors.forename: Hwi-yeol
authors.initials: HY
authors.lastname: Yun
authors.forename: Kwang-il
authors.initials: KI
authors.lastname: Kwon
mesh_terms: D000818:Animals; D016589:Astemizole / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology*; D016001:Confidence Intervals; D004285:Dogs; D004562:Electrocardiography; D008297:Male; D008955:Models, Cardiovascular
chemical_list: D016589:Astemizole
keywords: Astemizole; NONMEM; PK/PD modeling; QT prolongation; circadian rhythm