Pharmacokinetics and Safety of Vortioxetine in Pediatric Patients.
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.


CONCLUSIONS
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.
1 Department of Psychiatry and Behavioral Sciences, Kennedy Krieger Institute and Johns Hopkins University , Baltimore, Maryland.
Robert L
RL
Findling
2 Department of Psychology and Behavioral Health, Children's National Health Systems , Washington, District of Columbia.
Adelaide S
AS
Robb
3 Department of Psychiatry and Behavioral Neuroscience, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio.
Melissa
M
DelBello
4 Universitätsmedizin , Klinik für Kinder- und Jugendpsychiatrie und -Psychotherapie, Mainz, Germany .
Michael
M
Huss
5 University Hospitals Case Medical Center , Cleveland, Ohio.
Nora
N
McNamara
6 Sarkis Family Psychiatry, Gainesville, Florida.
Elias
E
Sarkis
7 Department of Psychiatry and Behavioral Sciences, University of Kansas School of Medicine , Wichita, Kansas.
Russell
R
Scheffer
8 H. Lundbeck A/S, Valby, Denmark .
Lis H
LH
Poulsen
9 Clinical Pharmacology, Takeda Development Center Americas , Deerfield, Illinois.
Grace
G
Chen
8 H. Lundbeck A/S, Valby, Denmark .
Ole Michael
OM
Lemming
8 H. Lundbeck A/S, Valby, Denmark .
Johan
J
Areberg
8 H. Lundbeck A/S, Valby, Denmark .
Philippe
P
Auby
D000293:Adolescent; D014151:Anti-Anxiety Agents / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001008:Anxiety Disorders / Q000097:blood / Q000188:drug therapy / Q000453:epidemiology; D001289:Attention Deficit Disorder with Hyperactivity / Q000097:blood / Q000188:drug therapy / Q000453:epidemiology; D002648:Child; D015897:Comorbidity; D003866:Depressive Disorder / Q000097:blood / Q000188:drug therapy / Q000453:epidemiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D010879:Piperazines / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013440:Sulfides / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000078784:Vortioxetine
D014151:Anti-Anxiety Agents; D010879:Piperazines; D013440:Sulfides; D000078784:Vortioxetine
adolescents; adverse events; antidepressant; children; dosing; pharmacokinetics; vortioxetine