DRUG-RESPONSE RELATIONSHIP OF ESCITALOPRAM IN OBSESSIVE COMPULSIVE DISORDER BASED ON TREATMENT OUTCOME: A PHARMACOKINETIC-PHARMACODYNAMIC MODELING APPROACH

Abstract Background While selective serotonin reuptake inhibitors (SSRIs) are the established first-line treatment for obsessive compulsive disorder (OCD), substantial number of patients show unsatisfactory response. Effectiveness of high dose SSRIs has been reported, but evidences from randomized clinical trial is still limited. In the meantime, population pharmacokinetic-pharmacodynamic (PK-PD) model approach and model-based simulation might be useful in establishing time course of the dose-response relationship, whichthen can be utilized to predict treatment response. Aim and Objectives This study aimed to evaluate the time course of the relationship between plasma escitalopram concentration and treatment response measured by the Yale-Brown Obsessive Compulsive Scale (YBOCS) score by a simulation based on population PK-PD model. Methods The steady-state plasma escitalopram concentrations and 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 also used for the development of escitalopram PK model. The changes in YBOCS score after escitalopram treatment were described sequentially by a PD model using the predicted concentrations from the patient PK model. All the PK-PD models were developed using NONMEM® Results The escitalopram PK data from the patients and healthy volunteers were modeled using two- compartment model with a first-order absorption (Ka). The clearance of escitalopram for patients was estimated to be 43% lower than healthy subjects. The relationship between exposure to escitalopram and YBOCS score was described by an inhibitory Emax model with effect compartment model. Simulated relationship between escitalopram concentrations in effect compartment and YBOCS score of treatment responders and non-responders showed difference in dose-response relationship. Discussion and Conclusions The developed PK-PD model adequately describes the dose-response relationship of escitalopram and the improvement in YBOCS score in OCD adequately. The model-based simulation shows that the drug trial of adequate dose for sufficient duration and monitoring the plasma drug level is important when determining treatment response to escitalopram. The difference in dose-response relationship of escitalopram in patients with OCD according to treatment responsiveness imply the possibility of different neurobiologic mechanism underlying OCD patients who are not responding to the SSRI treatment.