title: Therapeutic drug monitoring of second-generation antipsychotics in pediatric patients: an observational study in real-life settings.
abstract: OBJECTIVE
  Available guidelines on therapeutic drug monitoring of second-generation antipsychotics were designed for adults; therefore, they cannot be transferred as such in pediatric patients, who may have different drug absorption, distribution, metabolism, and elimination. Moreover, available tools that guide dosing in neuropsychiatric pediatric patients are scant, leading to the possibility of reduced efficacy and/or increased risks of toxicity. Here we describe the results of observational therapeutic drug monitoring conducted in three pediatric neuropsychiatry units across Italy in 2012-2014, with the following aims: (1) to describe the distribution of plasma concentrations of second-generation antipsychotics in our pediatric patients and (2) to identify clinical covariates associated with plasma drug levels.
  
  
  METHODS
  Five hundred fifty-six plasma trough concentrations of the second-generation antipsychotics risperidone (plus 9-hydroxy-risperidone), aripiprazole, olanzapine, and quetiapine were measured from 172 pediatric outpatients overall. The distribution of drug concentrations was described and correlated with drug doses and clinical variables.
  
  
  RESULTS
  Risperidone plasma levels were lower than in adults (median 13.6 ng/ml), with a high inter-patient (78.9%) but lower intra-patient (34.2%) variability. In multiple regression analyses, risperidone plasma levels depended only on drug dose (p < 0.001). Aripiprazole plasma levels were similar to those described in adults (median 165.8 ng/ml) and were widely distributed, with an inter-patient variability of 81.1%, while the intra-patient variability was much lower (29.3%). Multiple regression analyses indicated that aripiprazole plasma levels were influenced by the daily doses (p < 0.001) and by the number of concomitant drugs (p < 0.01).
  
  
  CONCLUSIONS
  Our study described the distribution of plasma levels of SGAs in a real-life setting involving pediatric patients, significantly increasing the amount of available data for this fragile population. If confirmed in larger dataset, these data may contribute to the definition of optimal therapeutic window for risperidone and aripiprazole plasma levels in pediatric patients.
authors.affiliation: Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Lecco, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pozzi
authors.affiliation: Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, L. Sacco University Hospital, Università di Milano, 20157, Milan, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Cattaneo
authors.affiliation: Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, L. Sacco University Hospital, Università di Milano, 20157, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Baldelli
authors.affiliation: Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, L. Sacco University Hospital, Università di Milano, 20157, Milan, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Fucile
authors.affiliation: Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine, Second University of Naples, 80131, Naples, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Capuano
authors.affiliation: Department of Translational Medical Sciences, University Federico II of Naples, 80131, Naples, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Bravaccio
authors.affiliation: Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine, Second University of Naples, 80131, Naples, Italy.
authors.forename: Liberata
authors.initials: L
authors.lastname: Sportiello
authors.affiliation: Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Lecco, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Bertella
authors.affiliation: Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine, Second University of Naples, 80131, Naples, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Auricchio
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, School of Medicine, University of Catania, 95131, Catania, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Bernardini
authors.affiliation: Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine, Second University of Naples, 80131, Naples, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ferrajolo
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, School of Medicine, University of Catania, 95131, Catania, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Guastella
authors.affiliation: Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Lecco, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Mani
authors.affiliation: Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, L. Sacco University Hospital, Università di Milano, 20157, Milan, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Carnovale
authors.affiliation: Department of Mental and Physical Health and Preventive Medicine, Child and Adolescent Psychiatry Division, Second University of Naples, 80131, Naples, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Pisano
authors.affiliation: Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine, Second University of Naples, 80131, Naples, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Rafaniello
authors.affiliation: Department of Mental and Physical Health and Preventive Medicine, Child and Adolescent Psychiatry Division, Second University of Naples, 80131, Naples, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Riccio
authors.affiliation: Child and Adolescent Neuropsychiatry, Department of Medical and Paediatric Sciences, School of Medicine, University of Catania, 95131, Catania, Italy.
authors.forename: Renata
authors.initials: R
authors.lastname: Rizzo
authors.affiliation: Child and Adolescent Neuropsychiatry, Department of Medical and Paediatric Sciences, School of Medicine, University of Catania, 95131, Catania, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Scuderi
authors.affiliation: Department of Mental and Physical Health and Preventive Medicine, Child and Adolescent Psychiatry Division, Second University of Naples, 80131, Naples, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Sperandeo
authors.affiliation: Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Lecco, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Villa
authors.affiliation: Department of Mental and Physical Health and Preventive Medicine, Child and Adolescent Psychiatry Division, Second University of Naples, 80131, Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pascotto
authors.affiliation: Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Lecco, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Molteni
authors.affiliation: Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Department of Experimental Medicine, Second University of Naples, 80131, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Rossi
authors.affiliation: Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, L. Sacco University Hospital, Università di Milano, 20157, Milan, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Radice
authors.affiliation: Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Lecco, Italy. emilio.clementi@unimi.it.|Unit of Clinical Pharmacology, CNR Institute of Neuroscience, Department of Biomedical and Clinical Sciences, L. Sacco University Hospital, Università di Milano, 20157, Milan, Italy. emilio.clementi@unimi.it.
authors.forename: Emilio
authors.initials: E
authors.lastname: Clementi
mesh_terms: D000293:Adolescent; D014150:Antipsychotic Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000068180:Aripiprazole / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D001569:Benzodiazepines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D000077152:Olanzapine; D000069348:Quetiapine Fumarate / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D018967:Risperidone / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D014150:Antipsychotic Agents; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; D000068180:Aripiprazole; D018967:Risperidone; D000077152:Olanzapine
keywords: Aripiprazole; Pharmacokinetics; Risperidone; Second-generation antipsychotics; Therapeutic drug monitoring