Dataset Information

Pipamperone Population Pharmacokinetics Related to Effectiveness and Side Effects in Children and Adolescents.

ABSTRACT: BACKGROUND:Pipamperone is a frequently prescribed antipsychotic in children and adolescents in the Netherlands, Belgium, and Germany. However, pediatric pharmacokinetics and the relationship with side effects and efficacy are unknown. Currently, divergent pediatric dosing recommendations exist. OBJECTIVES:The objective of this study was to describe the population pharmacokinetics of pipamperone in children and adolescents; to correlate measured and predicted pipamperone trough concentrations and predicted 24-h area under the curves with effectiveness, extrapyramidal symptoms, and sedation; and to propose dose recommendations based on simulations. METHODS:Pipamperone concentrations were collected from Dutch pediatric patients in a prospective naturalistic trial (n?=?8), and German pediatric patients in a therapeutic drug monitoring service (n?=?22). A total of 70 pipamperone concentrations were used to develop a population pharmacokinetic model with non-linear mixed-effects modeling (NONMEM®). Additionally, an additional random sample of 21 German patients with 33 pipamperone concentrations from the same therapeutic drug monitoring service was used for external validation. Pharmacokinetic parameters were related to clinical improvement, sedation, and extrapyramidal symptoms. Simulations were performed to determine optimal dosages. RESULTS:In a one-compartment model, the apparent volume of distribution was 416 L/70 kg and the apparent clearance was 22.1 L/h/70 kg. Allometric scaling was used to correct for differences in bodyweight. The model was successfully externally validated. The median [25th-75th percentile] measured pipamperone trough concentrations were numerically higher in responders (98.0 µg/L [56.0-180.5 µg/L]) than in non-responders (58.0 µg/L [14.9-105.5 µg/L]), although non-significant (p?=?0.14). A twice-daily 0.6-mg/kg dosage was better than a fixed dosage to attain the concentration range observed in responders. CONCLUSIONS:Our findings suggest that pipamperone therapeutic reference ranges may be lower for children with behavioral problems than recommended for adults with psychotic symptoms (100-400 µg/L). When dosing pipamperone in children and adolescents, bodyweight should be taken into account.

SUBMITTER: Kloosterboer SM

PROVIDER: S-EPMC7658071 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pipamperone Population Pharmacokinetics Related to Effectiveness and Side Effects in Children and Adolescents.

Kloosterboer Sanne M SM Egberts Karin M KM de Winter Brenda C M BCM van Gelder Teun T Gerlach Manfred M Hillegers Manon H J MHJ Dieleman Gwen C GC Bahmany Soma S Reichart Catrien G CG van Daalen Emma E Kouijzer Mirjam E J MEJ Dierckx Bram B Koch Birgit C P BCP

Clinical pharmacokinetics 20201101 11

<h4>Background</h4>Pipamperone is a frequently prescribed antipsychotic in children and adolescents in the Netherlands, Belgium, and Germany. However, pediatric pharmacokinetics and the relationship with side effects and efficacy are unknown. Currently, divergent pediatric dosing recommendations exist.<h4>Objectives</h4>The objective of this study was to describe the population pharmacokinetics of pipamperone in children and adolescents; to correlate measured and predicted pipamperone trough con ...[more]

PMID: 32394297

Similar Datasets

Project description:AimRisperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the relationship of risperidone and 9-hydroxyrisperidone trough concentrations, maximum concentrations and 24-hour area under the curves (AUCs) with body mass index (BMI) z-scores in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side effects and effectiveness.MethodsForty-two children and adolescents (32 males) aged 6-18 years were included in a 24-week prospective observational trial. Drug plasma concentrations, side effects and effectiveness were measured at several time points during follow-up. Relevant pharmacokinetic covariates, including medication adherence and CYP2D6, CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) genotypes, were measured. Nonlinear mixed-effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 205 risperidone and 205 9-hydroxyrisperidone concentrations. Subsequently, model-based trough concentrations, maximum concentrations and 24-hour AUCs were analysed to predict outcomes using generalized and linear mixed-effects models.ResultsA risperidone two-compartment model combined with a 9-hydroxyrisperidone one-compartment model best described the measured concentrations. Of all the pharmacokinetic parameters, higher risperidone sum trough concentrations best predicted higher BMI z-scores during follow-up (P < .001). Higher sum trough concentrations also predicted more sedation (P < .05), higher prolactin levels (P < .001) and more effectiveness measured with Aberrant Behavior Checklist irritability score (P < .01).ConclusionOur results indicate a therapeutic window exists, which suggests that therapeutic drug monitoring of risperidone might increase safety and effectiveness in children and adolescents with ASD and behavioural problems.

Dataset Information

Pipamperone Population Pharmacokinetics Related to Effectiveness and Side Effects in Children and Adolescents.

Publications

Pipamperone Population Pharmacokinetics Related to Effectiveness and Side Effects in Children and Adolescents.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets