{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T18:40:59Z","timestamp":1784832059586,"version":"3.55.0"},"reference-count":12,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T00:00:00Z","timestamp":1749772800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>The clinical effectiveness of tezacaftor\u2010ivacaftor in children with cystic fibrosis (cwCF) varies; some patients respond while others do not or have adverse effects. The pharmacokinetics (PK) of tezacaftor\u2010ivacaftor are inadequately published, especially in children. Knowledge of the PK in this cohort in relation to clinical outcomes may give further insight into the drug's exposure\u2013response relationship and its associated interindividual variability. The aim of this study was to assess the real\u2010world PK of tezacaftor\u2010ivacaftor in cwCF.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A prospective, observational PK study was performed in cwCF using tezacaftor\u2010ivacaftor. PK samples were obtained by dried blood spots at home and during routine outpatient hospital visits. Population PK (popPK) models were created using nonlinear mixed\u2010effects modelling. Due to data scarcity, prior information from adolescent\/adult PK models was required.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The study involved 21 children (age 6\u201317\u2009years, weight 24\u201370\u2009kg). Novel popPK models were created for tezacaftor\u2010ivacaftor and its main metabolites. Variability in PK was explained by variation in body weight. The area under the curve of tezacaftor\u2010ivacaftor varied significantly within and across age groups, which corresponded to the reported area under the curve in the product information. Maximum concentration and elimination half\u2010lives closely matched adult reported values.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This is the first study to investigate the popPK of tezacaftor\u2010ivacaftor in cwCF. The established models can be used for more personalized dosing in children experiencing suboptimal efficacy, adverse effects, drug\u2013drug interactions, or where adherence is a concern.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bcp.70131","type":"journal-article","created":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T06:38:33Z","timestamp":1749796713000},"page":"2969-2978","source":"Crossref","is-referenced-by-count":1,"title":["Real\u2010world population pharmacokinetics of tezacaftor\u2010ivacaftor in children with cystic fibrosis: The SYM\u2010CF study"],"prefix":"10.1002","volume":"91","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9905-7805","authenticated-orcid":false,"given":"Steffie E. M.","family":"Vonk","sequence":"first","affiliation":[{"name":"Amsterdam UMC location University of Amsterdam Department of Hospital Pharmacy &amp; Clinical Pharmacology  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne W. J.","family":"Terheggen\u2010Lagro","sequence":"additional","affiliation":[{"name":"Amsterdam UMC location University of Amsterdam Emma Children's Hospital, Department of Pediatric Pulmonology and Allergy  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric G.","family":"Haarman","sequence":"additional","affiliation":[{"name":"Amsterdam UMC location University of Amsterdam Emma Children's Hospital, Department of Pediatric Pulmonology and Allergy  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hettie M.","family":"Janssens","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Respiratory Medicine and Allergology Erasmus MC\u2010Sophia Children's Hospital, University Medical Center Rotterdam  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke\u2010Hilse","family":"Maitland\u2013van der Zee","sequence":"additional","affiliation":[{"name":"Amsterdam UMC location University of Amsterdam Department of Pulmonary Medicine  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. Marleen","family":"Kemper","sequence":"additional","affiliation":[{"name":"Amsterdam UMC location University of Amsterdam Department of Hospital Pharmacy &amp; Clinical Pharmacology  Amsterdam The Netherlands"},{"name":"Amsterdam UMC location University of Amsterdam Department of Vascular Medicine  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron A. A.","family":"Math\u00f4t","sequence":"additional","affiliation":[{"name":"Amsterdam UMC location University of Amsterdam Department of Hospital Pharmacy &amp; Clinical Pharmacology  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Amsterdam Mucociliary Clearance Disease (AMCD) research group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,13]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32542-3"},{"key":"e_1_2_10_3_1","volume-title":"Nederlandse CF Registratie Jaarrapport 2022","author":"NCFS","year":"2023"},{"key":"e_1_2_10_4_1","volume-title":"Summary of product characteristics \u2010 SYMKEVI","author":"EMA","year":"2018"},{"key":"e_1_2_10_5_1","unstructured":"FDA.CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW SYMDEKO (TEZACAFTOR\/IVACAFTOR).201728\u201006\u20102017."},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2019.06.009"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-020-09695-z"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0000000000000829"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0000000000001231"},{"key":"e_1_2_10_10_1","unstructured":"FDA.CLINICAL PHARMACOLOGY REVIEW KALYDECO (IVACAFTOR).201227\u201001\u20102012."},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0000000000000246"},{"key":"e_1_2_10_12_1","volume-title":"Clinical pharmacokinetics and pharmacodynamics","author":"Rowland MTTN","year":"2011"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcte.2021.100270"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bcp.70131","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T07:31:15Z","timestamp":1758871875000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1002\/bcp.70131"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,13]]},"references-count":12,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1002\/bcp.70131"],"URL":"https:\/\/doi.org\/10.1002\/bcp.70131","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"value":"0306-5251","type":"print"},{"value":"1365-2125","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,13]]}}}