Pipamperone Population Pharmacokinetics Related to Effectiveness and Side Effects in Children and Adolescents
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ORIGINAL RESEARCH ARTICLE
Pipamperone Population Pharmacokinetics Related to Effectiveness and Side Effects in Children and Adolescents Sanne M. Kloosterboer1,2 · Karin M. Egberts3 · Brenda C. M. de Winter1 · Teun van Gelder1 · Manfred Gerlach3 · Manon H. J. Hillegers2 · Gwen C. Dieleman2 · Soma Bahmany1 · Catrien G. Reichart4 · Emma van Daalen5 · Mirjam E. J. Kouijzer6 · Bram Dierckx2 · Birgit C. P. Koch1
© The Author(s) 2020
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.
1 Introduction Pipamperone is one of the most frequently prescribed antipsychotics for children and adolescents in the Netherlands, Germany, and Belgium [1–3]. Between 2005 and 2015, 18% of all antipsychotics prescribed to children and adolescents Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40262-020-00894-y
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