The effect of reporting methods for dosing times on the estimation of pharmacokinetic parameters of escitalopram

摘要

The objective of this study was to compare population pharmacokinetic (PPK) models of escitalopram developed from dosage times recorded by a medication event monitoring system (MEMS) versus the reported times from patients with diagnosed depression. 73 patients were prescribed doses of 10,15 or 20 mg of 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 PPK model based on dosing records obtained from MEMS prior to each blood sample time. A separate PPK 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 (OFV) 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 hrs. A one 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/hr). 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 Ka (MEMS vs. Patient reported: 0.74 (45.7%) vs. 0.51 (35.4%) hr⁻¹) for escitalopram. Furthermore, the parameters estimated from the MEMS method were similar to literature reported values for V/F (∼1100L) and Ka (∼ 0.8−0.9 hr⁻¹) arising from traditional PK approaches.