{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T19:38:06Z","timestamp":1790969886056,"version":"4.1.0"},"reference-count":25,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp;amp; Syst Pharma"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Pediatric physiologically\u2010based pharmacokinetic (PBPK) modelling plays an increasing role in selecting doses in children and addressing clinical pharmacology questions. Ethical concerns often limit clinical pharmacology studies that have no direct therapeutic benefit in children, highlighting the value of PBPK model predictions. However, regulatory acceptance of pediatric PBPK models remains limited because of uncertainties in system\u2010specific information and inadequate model qualification. Ambiguous ontogeny data of drug metabolizing enzymes (DME) and transporters are recognized as significant obstacles to the accurate pharmacokinetics (PK) prediction in children and the leading cause of insufficient pediatric PBPK model qualification. To address this challenge, a population PBPK modeling approach is proposed. This method is analogous to whole\u2010body PBPK modeling and allows the estimation of DME\/transporter ontogenies using sparse PK data collected from children and adults by nonlinear mixed\u2010effect modeling. Well\u2010characterized ontogeny functions of key DME\/transporters enhance the extrapolation ability of PBPK models and facilitate model\u2010informed drug development (MIDD) in children. This article proposes a strategy for pediatric PK extrapolation using population PBPK modeling, illustrated through the case example of risdiplam, approved for the treatment of spinal muscular atrophy. The ontogeny modeling, extrapolations of PK to unstudied pediatric populations, and drug\u2013drug interaction (DDI) risk assessment are also discussed. The population PBPK modeling approach is intended to address the inconsistencies in ontogeny data and augment PBPK modeling for quantitative clinical pharmacology assessments in children. It will accelerate optimal dose finding and provide guidance for adequate use of drugs in pediatric patients, which is especially important for developing treatments for progressive pediatric rare diseases.<\/jats:p>","DOI":"10.1002\/psp4.70174","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T09:25:49Z","timestamp":1769678749000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Population Physiologically\u2010Based Pharmacokinetic Modeling to Determine Ontogeny: A Quantitative Clinical Pharmacology Example in Pediatric Rare Disease"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9703-7269","authenticated-orcid":false,"given":"Yumi","family":"Cleary","sequence":"first","affiliation":[{"name":"Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences University of Manchester  Manchester UK"},{"name":"Roche Pharma Research and Early Development Pharmaceutical Sciences, Roche Innovation Center Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhagwat","family":"Prasad","sequence":"additional","affiliation":[{"name":"Division of Translational and Clinical Pharmacology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayode","family":"Ogungbenro","sequence":"additional","affiliation":[{"name":"Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Gertz","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development Pharmaceutical Sciences, Roche Innovation Center Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3933-5217","authenticated-orcid":false,"given":"Aleksandra","family":"Galetin","sequence":"additional","affiliation":[{"name":"Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,29]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40495-024-00362-2"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2384"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.4155\/ipk-2016-0025"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.116.069559"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1763"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-014-0140-7"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.585"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.2452"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.116.071159"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3719"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-023-00877-1"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-018-0277-7"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2134"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.449"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-014-1581-2"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-012-0918-y"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-018-2458-6"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-021-00595-9"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-023-01241-7"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-200202000-00018"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2010.03876.x"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.117.243113"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1493"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200645090-00005"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12798"}],"container-title":["CPT: Pharmacometrics &amp; 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