Seoyoung Kim1, Sungjeong Lee2, Dongwoo Kang1, Bo-Hyung Kim3,4, Euitae Kim1,5
(1) Department of Neuropsychiatry, Seoul National University Bundang Hospital, Republic of Korea (2) Department of Statistics, Inha University, Republic of Korea, (3) Department of Clinical Pharmacology and Therapeutics, Kyung Hee University Hospital, Republic of Korea (4) Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Republic of Korea (5) Department of Psychiatry, College of Medicine, Seoul National University, Republic of Korea
Objectives: The aim of this study was to develop pharmacokinetic-pharmacodynamic (PKPD) model of escitalopram concentration and its therapeutic effect on obsessive-compulsive symptom.
Methods: The steady-state plasma escitalopram concentrations and Yale-Brown Obsessive Compulsive Scale (YBOCS) scores from 91 patients who were enrolled in the prior escitalopram clinical trial were used in this analysis. Subjects were randomly assigned to two groups with different maintenance dose of escitalopram, 20 or 40mg. The serial plasma escitalopram concentrations from 12 healthy volunteers were used for the development of escitalopram PK model [1]. The changes in YBOCS score per escitalopram treatment were described sequentially by a PD model using the patient PK model predicted concentration. All the PKPD models were developed using NONMEM®.
Results: The escitalopram PK data from the patients and healthy volunteers were modeled using two-compartment model with a sequential zero-order drug input (D1) and first-order absorption (Ka). The clearance of escitalopram for patients was estimated to be 43% lower than healthy subjects. When developing patient PK model, a few parameters including absorption parameters were fixed at estimated values from healthy volunteer data because of very sparse PK sampling for patients, mostly only 2 samples from up to 136 days of treatment. The relationship between exposure from escitalopram maintenance dose and YBOCS score was described by an inhibitory model employing sigmoid Emax function of effect compartment concentration. The baseline YBOCS score (E0) was estimated to be 26.9, maximum decrease (Imax) and sigmoidicity, 52.8% and 1.53, respectively.
Conclusions: The developed PKPD model adequately describes the exposure response relationship of escitalopram and the improvement in YBOCS score.
References:
[1] Regional Differences in Serotonin Transporter Occupancy by Escitalopram: An [11C]DASB PK-PD Study. Clin Pharmacokinet. 2017 Apr;56(4):371-381
Reference: PAGE 28 (2019) Abstr 9029 [www.page-meeting.org/?abstract=9029]
Poster: Drug/Disease Modelling - CNS