Dataset Information

Pharmacokinetics and Safety of Vortioxetine in Pediatric Patients.

ABSTRACT: 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.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.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.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.

SUBMITTER: Findling RL

PROVIDER: S-EPMC5568018 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Pharmacokinetics and Safety of Vortioxetine in Pediatric Patients.

Findling Robert L RL Robb Adelaide S AS DelBello Melissa M Huss Michael M McNamara Nora N Sarkis Elias E Scheffer Russell R Poulsen Lis H LH Chen Grace G Lemming Ole Michael OM Areberg Johan J Auby Philippe P

Journal of child and adolescent psychopharmacology 20170323 6

<h4>Objective</h4>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.<h4>Methods</h4>This prospective, open-label, multinational, multisite, multiple-dose trial enrolled 48 patients (children and adolescents; 1:1 ratio) divided into 8 cohorts ...[more]

PMID: 28333546

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Project description:INTRODUCTION:Major depressive disorder (MDD) is associated with a significant burden of disease in China. Awareness and better access to treatments could help alleviate the burden associated with MDD. Because variations have been observed in the pharmacokinetics (PK) of antidepressants across different races and ethnicities, evaluation of the clinical pharmacology of vortioxetine in diverse populations remains important to assess the potential need for dose adjustments. METHODS:Data were pooled from two phase I open-label PK studies in healthy Chinese subjects, and one phase III double-blind noninferiority study in Chinese patients with MDD to describe the PK and safety data for vortioxetine. Doses in these studies ranged from 10 mg (single dose) to 10 and 20 mg (multiple daily doses). A population PK analysis of vortioxetine in the Chinese population was conducted using nonlinear mixed-effect modeling. RESULTS:In total, 186 individuals were included in the PK analysis: 79 healthy Chinese subjects and 107 Chinese patients with MDD. No clinically significant differences in the PK of vortioxetine were observed between the Chinese population and the previous data in non-Chinese populations. Because of a generally lower weight in the Chinese population compared with the non-Chinese population, exposures were 19% and 18% higher in the Chinese population than in the non-Chinese population (for maximum observed plasma concentration and area under the plasma concentration-time curve, respectively), which is not considered clinically relevant. A high prevalence of pruritus was observed in one phase I PK study (56% overall); however, this was not reflected in the phase III study in Chinese patients with MDD (0.8%). CONCLUSIONS:The PK parameters of vortioxetine in Chinese subjects were comparable to previous data in non-Chinese subjects. Overall, no new safety concerns were raised among the Chinese population. On the basis of this analysis, the tolerability profile of vortioxetine in Chinese healthy subjects and in patients with MDD is expected to be comparable to that in the non-Chinese population. FUNDING:H. Lundbeck A/S, Valby, Denmark. TRIAL REGISTRATION:NCT01676571.

Project description:ObjectivesThe aim of this study was to evaluate the pharmacokinetic (PK) profile, safety, and efficacy of gadopiclenol, a new high-relaxivity gadolinium-based contrast agent, in children aged 2 to 17 years.Materials and methodsChildren scheduled to undergo contrast-enhanced magnetic resonance imaging of the central nervous system (CNS cohort) or other organs (body cohort) were included sequentially into 3 age groups (12-17, 7-11, and 2-6 years). Gadopiclenol was administered at the dose of 0.05 mmol/kg. A sparse sampling approach was applied, with 4 blood samples per child collected up to 8 hours postinjection. Population PK modeling was used for the analysis, including the CNS cohort and adult subjects from a previous study. Adverse events were recorded, and efficacy was assessed for all children.ResultsEighty children were included, 60 in the CNS cohort and 20 in the body cohort. The 2-compartment model with linear elimination from the central compartment developed in adults was also suitable for children. Pharmacokinetic parameters were very similar between adults and children. Terminal elimination half-life was 1.82 hours for adults and 1.77 to 1.29 hours for age groups 12-17 to 2-6 years. The median clearance ranged from 0.08 L/h/kg in adults and 12-17 years to 0.12 L/h/kg in 2-6 years. The median central and peripheral volumes of distribution were 0.11 to 0.12 L/kg and 0.06 L/kg, respectively, for both adults and children. Simulations of plasma concentrations showed minor differences, and median area under the curve was 590 mg·h/L for adults and 582 to 403 mg·h/L for children. Two patients (2.5%) experienced nonserious adverse events considered related to gadopiclenol: a mild QT interval prolongation and a moderate maculopapular rash. Despite the limited number of patients, this study showed that gadopiclenol improved lesion detection, visualization, and diagnostic confidence.ConclusionsThe PK profile of gadopiclenol in children aged 2 to 17 years was similar to that observed in adults. Thus, there is no indication for age-based dose adaptation, and comparable plasma gadopiclenol concentrations are predicted to be achieved with body weight-based dosing in this population. Gadopiclenol at 0.05 mmol/kg seems to have a good safety profile in these patients and could improve lesion detection and visualization, therefore providing better diagnostic confidence.

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Pharmacokinetics and Safety of Vortioxetine in Pediatric Patients.

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Pharmacokinetics and Safety of Vortioxetine in Pediatric Patients.

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