K. Shin (1), E. Kim (2), S. Kim (2), J. Kwon (2), Y. Cha (1), H. Ahn (1), K. Lim (1), J. Chung (1), K. Yu (1), I. Jang (1)
(1) Department of Clinical Pharmacology & Therapeutics, Seoul National University College of Medicine & Hospital, Seoul, Korea; (2) Department of Psychiatry, Seoul National University Hospital, Seoul, Korea
Objectives: Pharmacokinetic-pharmacodynamic (PK-PD) modeling has been suggested for the prediction of brain receptor occupancy by antipsychotics. Escitalopram, a selective serotonin reuptake inhibitor, is used for depression or obsessive-compulsive disorder (OCD). This study aimed to assess escitalopram PK and PD profile using positron emission tomography (PET) data in healthy volunteers to explore the relationship between plasma drug concentration and transporter occupancy.
Methods: The population PK and PD analysis was performed using nonlinear mixed effect model (NONMEM® VII) based on plasma concentrations and transporter occupancies from PET imaging in healthy volunteers receiving escitalopram 5-20 mg dose range. Sequential PK-PD model was developed and the first-order conditional estimation in NONMEM was employed for model run. A one-compartment model with first order absorption and first-order elimination described the PK. The influence of demographic characteristics on PK parameters was examined. The serotonin transporter occupancy was calculated from binding potential of PET imaging. A sigmoid Emax model was employed to describe transporter occupancy by escitalopram in the caudate nucleus.
Results: Twelve subjects contributed to 144 escitalopram concentrations and 139 binding potential data for caudate. Oral clearance was 34.7 L/h (CV 35.1%), oral volume of distribution was 1280 L (CV 10.4%) and the absorption rate constant was 3.22 hr-1 (CV 68.7%). Of the covariates including age, weight, height evaluated, none of the covariate showed an influence on escitalopram PK parameters. The transporter occupancy in the caudate was correlated with escitalopram concentration. Sigmoid Emax model was well fitted for transporter occupancy in the caudate nucleus. EC50 was 1.67 ng/mL (CV 0.01%) and Hill coefficient was 0.681 (CV 25.9%).
Conclusions: PK-PD model for escitalopram was developed for healthy volunteers. Therapeutically effective serotonin transporter occupancy for OCD is unclear although that for depression was reported about 80% [1]. Further PK-PD modeling using occupancy for escitalopram may be useful tool to predict clinically relevant plasma concentration and drug effect in OCD patients.
References:
[1] M Kreilgaard et al, Br J Pharmacol. 2008 155(2):276-284
Reference: PAGE 21 () Abstr 2367 [www.page-meeting.org/?abstract=2367]
Poster: CNS