{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:45:55Z","timestamp":1786977955374,"version":"build-2736575974"},"reference-count":26,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2023,1,29]],"date-time":"2023-01-29T00:00:00Z","timestamp":1674950400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004330","name":"GlaxoSmithKline","doi-asserted-by":"publisher","award":["NCT01332331"],"award-info":[{"award-number":["NCT01332331"]}],"id":[{"id":"10.13039\/100004330","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>This study aimed to develop a population pharmacokinetic (PK) model of ambrisentan in pediatric patients (8 to &lt;18 years) with pulmonary arterial hypertension (PAH) and compare pediatric ambrisentan systemic exposure with previously reported adult data. Association of ambrisentan exposure with efficacy (6\u2010minute walking distance) and safety (adverse events) were exploratory analyses. A population PK model was developed using pediatric PK data. Steady\u2010state systemic exposure metrics were estimated for the pediatric population and compared with previously reported data in adult patients with PAH and healthy subjects. No covariates had a significant effect on PK parameters; therefore, the final covariate model was the same as the base model. The pediatric population PK model was a 2\u2010compartment model including the effect of body weight (allometric scaling),\u00a0first\u2010order absorption and elimination, and absorption lag time. Steady\u2010state ambrisentan exposure was similar between the pediatric and adult population when accounting for body weight differences. Geometric mean area under the concentration\u2010time curve at steady state in pediatric patients receiving ambrisentan low dose was 3% lower than in the adult population (and similar in both populations receiving high dose). Geometric mean maximum plasma concentration at steady state in pediatric patients receiving low and high doses was 11% and 18% higher, respectively, than in the adult population. There was no apparent association in the pediatric or adult population between ambrisentan exposure and change in 6\u2010minute walking distance or incidence of ambrisentan\u2010related adverse events in pediatric patients. The similar ambrisentan exposure and exposure\u2013response profiles observed in pediatric and adult populations with PAH suggests appropriateness of body\u2010weight\u2013based dosing in the pediatric population with PAH.<\/jats:p>","DOI":"10.1002\/jcph.2199","type":"journal-article","created":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T04:23:46Z","timestamp":1672287826000},"page":"593-603","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Pediatric Population Pharmacokinetic Modeling and Exposure\u2013Response Analysis of Ambrisentan in Pulmonary Arterial Hypertension and Comparison With Adult Data"],"prefix":"10.1002","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4739-4989","authenticated-orcid":false,"given":"Malek","family":"Okour","sequence":"first","affiliation":[{"name":"Clinical Pharmacology Modeling and Simulation  GSK Collegeville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mita M.","family":"Thapar","sequence":"additional","affiliation":[{"name":"ICON Clinical Research  Reading Berkshire UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colm","family":"Farrell","sequence":"additional","affiliation":[{"name":"ICON Clinical Research  Reading Berkshire UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Ann","family":"Lukas","sequence":"additional","affiliation":[{"name":"Metabolic Pathways and Cardiovascular Therapeutic Area  GSK Collegeville Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurice","family":"Beghetti","sequence":"additional","affiliation":[{"name":"Pediatric Cardiology Unit University Children's Hospital Pulmonary Hypertension Program University of Geneva and Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque P\u00e9diatrique (CURCCCP) University of Geneva and Lausanne  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misba","family":"Beerahee","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Modeling and Simulation  GSK Stevenage Hertfordshire UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,1,29]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra040291"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01916-2018"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2015.08.080"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1203\/PDR.0b013e318179954c"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.016667"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.005698"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9236(03)00005-5"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2009.03532.x"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14039"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01032-2015"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1177\/1753465817696040"},{"key":"e_1_2_10_13_1","unstructured":"Food and Drug Administration (FDA).Ambrisentan prescribing information.2015. Accessed March 16 2021.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2015\/022081s033lbl.pdf."},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.22555"},{"issue":"2020","key":"e_1_2_10_15_1","article-title":"A randomized study of safety and efficacy of two doses of ambrisentan to treat pulmonary arterial hypertension in pediatric patients aged 8 years up to 18 years","volume":"5","author":"Ivy D","year":"2020","journal-title":"J Pediatr: X"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.281053"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2009.04.012"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.08-1028"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2009.07.033"},{"key":"e_1_2_10_20_1","unstructured":"ICON. NONMEM\u00ae 7.4. 2017. Accessed March 16 2021https:\/\/www.iconplc.com\/innovation\/nonmem\/."},{"key":"e_1_2_10_21_1","volume-title":"A language and environment for statistical computing","author":"R Core Team","year":"2013"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.742510"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1413687"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1177\/2045894020979503"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2015-309103"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.4103\/0022-3859.159421"},{"key":"e_1_2_10_27_1","unstructured":"GlaxoSmithKline.Volibris: EPAR\u2010Product Information; Annex 1: Summary of Product Information.2021. Accessed April 2022.https:\/\/www.ema.europa.eu\/en\/documents\/product\u2010information\/volibris\u2010epar\u2010product\u2010information_en.pdf."}],"container-title":["The Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.2199","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcph.2199","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.2199","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T23:42:42Z","timestamp":1692661362000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/jcph.2199"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,29]]},"references-count":26,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2023,5]]}},"alternative-id":["10.1002\/jcph.2199"],"URL":"https:\/\/doi.org\/10.1002\/jcph.2199","archive":["Portico"],"relation":{},"ISSN":["0091-2700","1552-4604"],"issn-type":[{"value":"0091-2700","type":"print"},{"value":"1552-4604","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,29]]},"assertion":[{"value":"2022-05-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-27","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-01-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}