Anhye Kim (1), Jaeseong Oh (1), Kyungho Jang (2), Su-jin Rhee (1), Kyung-Sang Yu (1), Howard lee (1)(3), In-Jin Jang (1), Jae-Yong Chung (4)
(1) Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea (2) Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine and CHA Bundang Medical Center, Seongnam, Korea (3) Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea (4) Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea
Objectives: Escitalopram had potential to prolong QT interval in dose-dependent manner and to show delayed QT interval prolongation [1]. To evaluate the QT interval induced by escitalopram, it is important to explain exposure-effect relationship based on a PK-PD modeling. This study aims to develop a PK/PD model of QT prolongation induced by escitalopram based on the data from the thorough QT (TQT) study and to evaluate effects of the escitalopram, placebo and sex on QT prolongation
Methods: PK and QTc data were obtained from previous TQT study in healthy volunteers (male/female) as follows: placebo 23/13 and escitalopram 21/12 [1]. The QT interval was individually adjusted (QTcI) for the heart rate for each subjects as follows: QTcI= QT/RRa (RR, the RR interval; a, an individually derived power term in the QT–RR regression). PK model of escitalopram was built using nonlinear mixed-effect model as implemented in NONMEM V7.3.0. For baseline correction, circadian effect (CIRC) on the baseline QTcI using cosine functions with up to two periods (12 and 6 hours) was explored based on the data from the placebo treatment. To explain delayed effect between PK and PD, the effect compartment model was employed. The PK-PD model included the drug and placebo effect, circadian rhythm and sex effect on QT prolongation.
Results: A one-compartment model with first-order absorption and lag time, first-order elimination and exponential error model was chosen as the final PK model for escitalopram. Circadian rhythm of baseline QTcI interval was well described. In the final PK-QTc model, QTcI interval was derived by the following equations; QTcI = (baseline of QTcI + Placebo effect + Sex) * (1 + CIRC) + slope of concentration-QTcI * concentration in effect compartment. According to the final PK-PD model, the maximal QTcI prolongation was estimated as 4.2 msec (slope (0.18 msec/ng/ml) multiplied by Cmax (23.1 ng/ml, [1]) ). The effect compartment equilibrium rate constant was 0.79 (1/h), and it explained a time delay between Cmax and maximal QTcI prolongation. The sex effect on QTcI prolongation was observed (+25.8 msec in female).
Conclusion: The present analysis was carried out as a follow-up study using observed data from the previous TQT study. The developed PK-PD model well described the time course of the QT interval and evaluated the effect of escitalopram on QTcI prolongation and hysteresis of escitalopram-induced QTc prolongation.
References:
[1] Kim, Anhye; Lim, Kyoung Soo; Lee, Howard; Chung, Hyewon; Yoon, Seo Hyun; Yu, Kyung-Sang; Cho, Joo-Youn; Jang, In-Jin; Chung, Jae-Yong; A thorough QT study to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine and escitalopram, in healthy volunteers, International Clinical Psychopharmacology, doi: 10.1097/YIC.0000000000000124
Reference: PAGE 25 (2016) Abstr 5824 [www.page-meeting.org/?abstract=5824]
Poster: Drug/Disease modeling - Safety