{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T04:27:23Z","timestamp":1788582443002,"version":"build-2803163510"},"reference-count":44,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T00:00:00Z","timestamp":1686614400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Aripiprazole is one of the most commonly prescribed antipsychotic drugs to children and adolescents worldwide, but it is associated with serious side\u2010effects, including weight gain. This study assessed the population pharmacokinetics of aripiprazole and its active metabolite and investigated the relationship between pharmacokinetic parameters and body mass index (BMI) in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side\u2010effects and drug effectiveness.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Twenty\u2010four children and adolescents (15 males, 9 females) aged 6\u201318\u2009years were included in a 24\u2010week prospective observational trial. Drug plasma concentrations, side\u2010effects and drug effectiveness were measured at several time points during follow\u2010up. Relevant pharmacokinetic covariates, including CYP2D6, CYP3A4, CYP3A5 and P\u2010glycoprotein (ABCB1) genotypes, were determined. Nonlinear mixed\u2010effects modelling (NONMEM\u00ae) was used for a population pharmacokinetic analysis with 92 aripiprazole and 91 dehydro\u2010aripiprazole concentrations. Subsequently, model\u2010based trough concentrations, maximum concentrations and 24\u2010h area under the curves (AUCs) were analysed to predict outcomes using generalized and linear mixed\u2010effects models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>For both aripiprazole and dehydro\u2010aripiprazole, one\u2010compartment models best described the measured concentrations, with albumin and BMI as significant covariates. Of all the pharmacokinetic parameters, higher sum (aripiprazole plus dehydro\u2010aripiprazole) trough concentrations best predicted higher BMI <jats:italic>z<\/jats:italic>\u2010scores (<jats:italic>P<\/jats:italic>\u00a0&lt;\u2009.001) and higher Hb1Ac levels (<jats:italic>P<\/jats:italic>\u00a0=\u2009.03) during follow\u2010up. No significant association was found between sum concentrations and effectiveness.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results indicate a threshold with regard to safety, which suggests that therapeutic drug monitoring of aripiprazole could potentially increase safety in children and adolescents with ASD and behavioural problems.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.15800","type":"journal-article","created":{"date-parts":[[2023,5,24]],"date-time":"2023-05-24T09:58:00Z","timestamp":1684922280000},"page":"3026-3036","source":"Crossref","is-referenced-by-count":8,"title":["Towards precision dosing of aripiprazole in children and adolescents with autism spectrum disorder: Linking blood levels to weight gain and effectiveness"],"prefix":"10.1111","volume":"89","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9622-2246","authenticated-orcid":false,"given":"Rebecca A.","family":"Hermans","sequence":"first","affiliation":[{"name":"Department of Hospital Pharmacy Erasmus Medical Center  Rotterdam The Netherlands"},{"name":"Department of Child and Adolescent Psychiatry\/Psychology Erasmus Medical Center  Rotterdam the Netherlands"},{"name":"Rotterdam Clinical Pharmacometrics Group Erasmus Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiaan D. T.","family":"Sassen","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy Erasmus Medical Center  Rotterdam The Netherlands"},{"name":"Rotterdam Clinical Pharmacometrics Group Erasmus Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2573-4636","authenticated-orcid":false,"given":"Sanne Maartje","family":"Kloosterboer","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy Erasmus Medical Center  Rotterdam The Netherlands"},{"name":"Department of Child and Adolescent Psychiatry\/Psychology Erasmus Medical Center  Rotterdam the Netherlands"},{"name":"Rotterdam Clinical Pharmacometrics Group Erasmus Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catrien G.","family":"Reichart","sequence":"additional","affiliation":[{"name":"LUMC\u2010Curium Child and Adolescent Psychiatry Leiden University Medical Center  Oegstgeest The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjam E. J.","family":"Kouijzer","sequence":"additional","affiliation":[{"name":"GGz Breburg, Centre of Youth  Breda the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias M. J.","family":"de Kroon","sequence":"additional","affiliation":[{"name":"de Kroon Child Psychiatry  Breda the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Bastiaansen","sequence":"additional","affiliation":[{"name":"Yulius Mental Health  Dordrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daphne","family":"van Altena","sequence":"additional","affiliation":[{"name":"Department of Youth GGZ Delfland  Delft The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron H. N.","family":"van Schaik","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry Erasmus University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5666-5015","authenticated-orcid":false,"given":"Kazem","family":"Nasserinejad","sequence":"additional","affiliation":[{"name":"Department of Hematology Erasmus Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon H. J.","family":"Hillegers","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry\/Psychology Erasmus Medical Center  Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1202-3643","authenticated-orcid":false,"given":"Birgit C. P.","family":"Koch","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy Erasmus Medical Center  Rotterdam The Netherlands"},{"name":"Rotterdam Clinical Pharmacometrics Group Erasmus Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bram","family":"Dierckx","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry\/Psychology Erasmus Medical Center  Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda C. M.","family":"de Winter","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy Erasmus Medical Center  Rotterdam The Netherlands"},{"name":"Rotterdam Clinical Pharmacometrics Group Erasmus Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,6,13]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.books.9780890425596"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10803\u2010006\u20100147\u20105"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/aur.2696"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2015\u20102851K"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/JCP.0b013e3182549259"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eurpsy.2010.09.011"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1089\/cap.2008.007"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2013.2053"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2020.550201"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0b013e318178e18d"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00702\u2010020\u201002253\u20104"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1089\/cap.2008.0111"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/JCP.0b013e31817dd520"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228\u2010015\u20101982\u20100"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.books.9780890423349"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0000000000000502"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0000000000000411"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/bmc.3610"},{"key":"e_1_2_10_20_1","volume-title":"ECDEU Assessment Manual for Psychopharmacology","author":"Guy W","year":"1976"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/14.6.540"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2008.03.037"},{"issue":"5","key":"e_1_2_10_23_1","first-page":"485","article-title":"The aberrant behavior checklist: a behavior rating scale for the assessment of treatment effects","volume":"89","author":"Aman MG","year":"1985","journal-title":"Am J Ment Defic"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2008\u20101349"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.23574"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1000171"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095\u2010012\u20100668\u2010x"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.clpt.6100241"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1552\u20104604.1997.tb04326.x"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmpb.2007.12.002"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.2471\/BLT.07.043497"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ijo.0803175"},{"key":"e_1_2_10_33_1","volume-title":"Second International Symposium on Information Theory","author":"Akaike H","year":"1973"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14465"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1080\/03602532.2020.1717517"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.5414\/CP202466"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365\u20102125.2008.03223.x"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928\u2010015\u20109414\u20104"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.30.2154"},{"key":"e_1_2_10_40_1","unstructured":"Aripiprazole Sandoz 10mg tablets\u2014Summary of Product Characteristics (SmPC).2021. Accessed May 28 2023.https:\/\/www.medicines.org.uk\/emc\/product\/7016\/smpc"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13259"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2011.03.020"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399\u20105618.2007.00534.x"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2018.1088"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8111336"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcp.15800","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T06:09:19Z","timestamp":1698041359000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bcp.15800"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,13]]},"references-count":44,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2023,10]]}},"alternative-id":["10.1111\/bcp.15800"],"URL":"https:\/\/doi.org\/10.1111\/bcp.15800","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"value":"0306-5251","type":"print"},{"value":"1365-2125","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,13]]}}}