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The Effect of Reporting Methods for Dosing Times on the Estimation of Pharmacokinetic Parameters of Escitalopram

From the Department of Pharmaceutical Sciences (Ms Jin, Dr Florian, Dr Bies) and Department of Psychiatry (Dr Pollock, Dr Frank, Ms Kirshner, Dr Fagiolini, Dr Kupfer, Ms Kepple, Dr Bies), University of Pittsburgh, Pittsburgh, Pennsylvania; Rotman Research Institute, University of Toronto, Ontario, Canada (Dr Pollock); Metrum Institute, Tariffville, Connecticut (Dr Gastonguay); and Strategic Modeling and Simulation, BMS, Princeton, New Jersey (Dr Feng).

The objective of this study was to compare population pharmacokinetic models of escitalopram developed from dosage times recorded by a medication event monitoring system (MEMS) versus the reported times from patients with diagnosed depression. Seventy-three patients were prescribed doses of 10, 15, or 20 mg escitalopram daily. Sparse blood samples were collected at weeks 4, 12, 24, and 36 with 185 blood samples obtained from the 73 patients. NONMEM was used to develop a population pharmacokinetic model based on dosing records obtained from MEMS prior to each blood sample time. A separate population pharmacokinetic analysis using NONMEM was performed for the same population using the patient-reported last dosing time and assuming a steady-state condition as the model input. Objective function values and goodness-of-fit plots were used as model selection criteria. The absolute mean difference in the last dosing time between MEMS and patient-reported times was 4.48 ± 10.12 hours. A 1-compartment model with first-order absorption and elimination was sufficient for describing the data. Estimated oral clearance (CL/F) to escitalopram was statistically insensitive to reported dosing methods (MEMS vs patient reported: 25.5 [7.0%] vs 26.9 [6.6%] L/h). However, different dosing report methods resulted in significantly different estimates on the volume of distribution (V/F; MEMS vs patient reported: 1000 [17.3%] vs 767 [17.5%] L) and the absorption rate constant K_a (MEMS vs patient reported: 0.74 [45.7%] vs 0.51 [35.4%] h^-1) for escitalopram. Furthermore, the parameters estimated from the MEMS method were similar to literature reported values for V/F (1100 L) and K_a (0.8-0.9 h^-1) arising from traditional pharmacokinetic approaches.

Key Words: Medication event monitoring system (MEMS) • population pharmacokinetics • escitalopram • selective serotonin reuptake inhibitors (SSRI) • antidepressant

Address for reprints: Robert R. Bies, PharmD, PhD, University of Pittsburgh Medical Center, Department of Pharmaceutical Sciences and Psychiatry, 805 Salk Hall, Pittsburgh, PA 15261; e-mail: rrb47{at}pitt.edu.

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