Population pharmacokinetic meta-analysis of vortioxetine in healthy individuals

Abstract

The objective was to describe the pharmacokinetics of vortioxetine and evaluate the effect of intrinsic and extrinsic factors in the healthy population. Data from 26 clinical pharmacology studies were pooled. A total of 21,758 vortioxetine quantifiable plasma concentrations were collected from 887 subjects with corresponding demography. The doses ranged from 2.5 to 75 mg (single dose) and 2.5-60 mg (multiple QD doses). The pharmacokinetics of vortioxetine was best characterised by a two-compartment model with first-order absorption, lag-time and linear elimination, with interindividual error terms for absorption rate constant, oral clearance and central volume of distribution. The population mean was 32.7 L/hr for oral clearance and 1.97∙10(3) L for the central volume of distribution. The average elimination half-life was 65.8 hr. CYP2D6 inferred metabolic status (ultra, extensive, intermediate or poor metabolisers) and age on oral clearance and height on central volume of distribution were identified as statistically significant covariate-parameter relationships. For CYP2D6 poor metabolisers, CL/F was approximately 50% to that seen in CYP2D6 extensive metabolisers. The impact of height on V2/F and age on CL/F was low and not considered to be clinically relevant. The final model was found to be reliable, stable and predictive. A reliable, stable and predictive pharmacokinetic model was developed to characterise pharmacokinetics of vortioxetine in the healthy population.

Fig 1

Structural model used for the population pharmacokinetic analysis of vortioxetine.

Fig 2

Goodness-of-fit plots for the final population pharmacokinetic model for vortioxetine in healthy individuals.

Fig 3

CYP2D6-inferred metabolic status (UM, ultra metaboliser; EM, extensive metaboliser; IM, intermediate metaboliser; PM, poor metaboliser) versus oral clearance (CL/F) for vortioxetine. Two subjects with CL/F values over 150 L/hr are excluded from the plot in order to improve readability.

Fig 4

Fraction of healthy individuals reaching 90% steady state versus days of dosing of vortioxetine.

Fig 5

Visual predictive check (VPC) plot for the final population pharmacokinetic model for vortioxetine in healthy individuals. Dose-normalised observed data (dots) and median, 2.5% and 97.5% percentiles for simulated data (solid lines) and dose-normalised observed data (dotted lines) are shown. The insert shows the first 20 hr after dosing.