Pharmacokinetics and Safety of Vortioxetine in Pediatric Patients

Abstract

Objective: The primary objectives of this study were to evaluate the pharmacokinetics (PK) and tolerability of single and multiple doses of vortioxetine in children and adolescents with a depressive or anxiety disorder and to provide supportive information for appropriate dosing regimens for pediatric clinical trials.Methods: This prospective, open-label, multinational, multisite, multiple-dose trial enrolled 48 patients (children and adolescents; 1:1 ratio) divided into 8 cohorts (4 adolescent and 4 child), with each cohort including 6 patients. The cohorts in each age group were assigned to receive one of four dosing regimens: vortioxetine 5, 10, 15, or 20 mg q.d. for 14 days. The total treatment period lasted 14–20 days with patients in the higher dose cohorts uptitrated over 2–6 days. Plasma samples for PK analysis were obtained on the first and last days of dosing.Results: Among children and adolescents, respectively, 62% and 92% had depression and 58% and 33% had anxiety disorder. Comorbid attention-deficit/hyperactivity disorder (ADHD) was present in 50% of children and 38% of adolescents. After 14 days q.d. at the target dose, the PK of vortioxetine concentrations was generally proportional to the dose in both age groups. Exposure, as assessed by maximum plasma concentrations and area under the plasma concentration–time curve from time 0 to 24 hours, was 30%–40% lower in adolescents than in children. There was no significant relationship between sex, height, or ADHD diagnosis and PK parameters. Most adverse events were mild in severity and consistent with those seen in adults.Conclusion: The results suggest that the dosages of vortioxetine evaluated (5–20 mg q.d.; approved for treatment in adults) and the uptitration schedule used are appropriate for pediatric efficacy and safety trials.

A 6-Month Open-Label Extension Study of Vortioxetine in Pediatric Patients with Depressive or Anxiety Disorders

“…Most patients from the lead-in period continued into the OLE, and the results provide further evidence that vortioxetine 5–20 mg/day is generally safe and well tolerated and is associated with continued effectiveness in children (aged 7–11 years) and adolescents (aged 12–17 years) with a depressive and/or anxiety disorder. The findings of this extension study are consistent with those of the lead-in period, which concluded that an uptitrated dosing strategy of vortioxetine 5–20 mg/day is suitable for future clinical studies of vortioxetine in pediatric patients (Findling et al 2017 ).…”

“…Detailed inclusion and exclusion criteria for participation in the lead-in study were described previously (Findling et al 2017 ). Briefly, pediatric outpatients aged 7–17 years (inclusive) were eligible at screening if they had a Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition, Text Revision ( DSM-IV-TR ™), diagnosis of a depressive or anxiety disorder that (as judged by the investigator) warranted antidepressant therapy.…”

“…Each cohort was assigned to receive vortioxetine, 5, 10, 15, or 20 mg, once daily for 14 days, with uptitration every 2 days for those assigned to higher dosages. Results of the 14-day lead-in period have been published and suggest that the exposure, safety, and tolerability of vortioxetine are similar to those in adults when an uptitration scheme is used to achieve higher doses (Findling et al 2017 ).…”

“…In response to regulatory requests, the first international pediatric pharmacokinetic/safety study with vortioxetine was conducted to determine if the dose range approved for adult patients (5–20 mg/day) is appropriate for pediatric efficacy and safety studies ( identifier: NCT01491035; EudraCT number: 2010-020170-42) (Findling et al 2017 ). The objectives of the lead-in study—a prospective, multinational, multisite, 14-day, open-label, multiple-dose pharmacokinetic/safety trial of vortioxetine, 5–20 mg/day, in pediatric patients—were to assess the pharmacokinetics, safety, and tolerability of vortioxetine across the dose range, providing data for evidence-based dosing strategies for future pediatric studies.…”

New Antidepressant Medication: Benefits Versus Adverse Effects

“…• There are no necessary dose adjustments in patients with mild to moderate renal or hepatic impairment or on the basis of patient age, sex, and race. Yet its efficacy and safety have not been sufficiently studied in children or adolescents, and it is not approved for pediatric patients; nevertheless, some recent results in acute therapy are promising [91,[96][97][98].…”