PK and safety data included in this post hoc analysis were pooled from two phase I open-label vortioxetine PK studies in healthy Chinese subjects and from one phase III double-blind, noninferiority study in Chinese patients with MDD who were treated with vortioxetine .
Study 1 (Single-Dose PK Study)
This was a single-center, open-label PK study with a primary objective to determine the PK of vortioxetine after a single dose of 10 mg administered orally under fasting conditions in healthy Chinese men and women (Trial registration: www.ClinicalTrials.gov identifier, NCT01676571).
Study 2 (Single- and Multiple-Dose PK Study)
This was a randomized open-label, single-center, single-dose, and multiple-dose PK study with a primary objective to determine the PK parameters after 10- and 20-mg single-dose and 10- and 20-mg multiple-dose administration of vortioxetine in healthy Chinese men and women (Trial registration: www.ClinicalTrials.gov identifier, NCT02386488). In the single-dose part, 16 male and 16 female subjects were randomized 1:1 to receive a single oral dose of 10 or 20 mg of vortioxetine on day 1. In the multiple-dose part, 16 male and 16 female subjects were randomized 1:1 to receive an oral dose of 10 or 20 mg of vortioxetine, respectively, each day for 14 consecutive days. Safety and tolerability were assessed throughout the study.
Study 3 (Active Comparator Noninferiority Study)
This was a multinational interventional, multicenter, randomized, double-blind, parallel-group, fixed-dose, active-comparator noninferiority study in patients with MDD (Trial registration: www.ClinicalTrials.gov identifier, NCT01571453). The study included 443 randomized patients recruited from 31 psychiatric inpatient and outpatient specialist settings in four countries (China, South Korea, Taiwan, and Thailand) from April 2012 to October 2013. Of note, only the PK and safety results from the 124 Chinese patients treated with vortioxetine were included in the current study’s pooled analyses. Efficacy results from the study have been published previously .
Study details for all three studies are summarized in Table 1.
For studies 1 and 2, participants were screened for enrollment from 21 to 2 days before treatment. Participants who met the inclusion criteria for each study were eligible for trial participation: men and women aged between 18 and 45 years; body weight at least 50 kg (study 1) or at least 45 kg (study 2); and body mass index between 19 and 24 kg/m2 (study 1) or between 18.5 and 24 kg/m2 (study 2). Major exclusion criteria in studies 1 and 2 included the following: disallowed medication taken less than 1 week before the first dose of study drug, or less than 5 half-lives before the screening visit for any medication taken; clinically significant comorbidities that might complicate treatment or potentially confound the study results; known hypersensitivity or allergies to medications; or clinically significant vital sign, laboratory test, or electrocardiogram abnormality at screening.
For study 3, participants were screened for enrollment from 7 days before treatment. Inclusion and exclusion criteria details for study 3 have been published previously . Briefly, patients with a primary diagnosis of recurrent MDD according to Diagnostic and Statistical Manual of Mental Disorders-IV-Text Revision (DSM-IV-TR™) criteria, a Montgomery–Åsberg Depression Rating Scale (MADRS) total score of at least 26, and a Clinical Global Impression–Severity (CGI-S) score of at least 4 with a reported duration of the current major depressive episode of at least 3 months were eligible. Participants were ineligible if they had any current anxiety disorder (DSM-IV-TR™ criteria) as assessed using the Mini International Neuropsychiatric Interview (MINI) or a current diagnosis or history of manic or hypomanic episode, schizophrenia, or any other psychotic disorder. Only the PK and safety results from the Chinese patients treated with vortioxetine (n = 124) in this study were included in the pooled analysis.
The population PK of vortioxetine were determined using nonlinear mixed-effect modeling with NONMEM® (ICON Development Solutions) version 7. The first-order conditional error with interaction (FOCE INTER) minimization method was used.
No formal statistically based strategy or rules for handling outliers among the plasma concentrations or covariate data were used. Visual inspection of the data was used to detect potential outliers to exclude from the analysis. The structural model used was a two-compartment model based on that previously described in the pooled-population PK analysis in healthy subjects  with lag time and with first-order absorption and elimination. The model, schematically shown in Fig. 1, was parameterized in terms of ALAG (lag time), ka (absorption rate constant), CL/F (oral clearance), V2/F (volume of distribution of central compartment), Q/F (intercompartmental clearance), and V3/F (volume of distribution of peripheral compartment).
The continuous covariates of age, weight, height, and creatinine clearance, and the categorical covariates of sex and healthy/patient were tested in the population PK model. Standard goodness-of-fit plots were generated to evaluate the fit of the base model to the data. Details of the visual predictive check plot and goodness-of-fit plots are provided in supplementary material. The model was evaluated using the normalized prediction distribution error and visual predictive check plots. The condition number was used to evaluate the stability of the model. The standard errors of the final model parameter values were estimated using the nonparametric bootstrap approach. The elimination half-life (t1/2) was estimated for each subject on the basis of the individual parameter values.
All treatment-emergent adverse events (TEAEs) either observed by the investigator or reported spontaneously by the patients and healthy subjects were recorded. Qualified personnel coded TEAEs using the lowest-level term according to the Medical Dictionary for Regulatory Activities (MedDRA), version 16.0. Clinical safety laboratory tests, vital signs, weight, body mass index, electrocardiograms, and physical examination findings were also evaluated.
Compliance with Ethics Guidelines
All study protocols were approved by the local ethics committees and were conducted in compliance with the International Conference for Harmonization, Harmonized Tripartite Guideline E6 for Good Clinical Practice. Enrolled participants for each study provided written informed consent before undergoing any study procedures.