{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:25:43Z","timestamp":1787199943150,"version":"build-2736575974"},"reference-count":43,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100002794","name":"Cancerfonden","doi-asserted-by":"publisher","award":["232921 Pj"],"award-info":[{"award-number":["232921 Pj"]}],"id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2024\/22\u20101325"],"award-info":[{"award-number":["2024\/22\u20101325"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Vincristine is a cornerstone of pediatric chemotherapy, but its use is limited by vincristine\u2010induced peripheral neuropathy (VIPN). Paradoxically, African children tolerate higher vincristine doses with minimal neurotoxicity, raising questions about the pharmacological mechanisms and model generalizability across populations. In this study, we re\u2010estimated vincristine pharmacokinetic (PK) and PK\u2010pharmacodynamic (PKPD) models using data from both Dutch and Kenyan pediatric cohorts and designed five simulation scenarios to assess the impact of Type I (informative censoring) and Type II (population\u2010specific effect modifier) selection bias on model predictions. A three\u2010compartment PK model with saturable distribution and a proportional\u2010odds PKPD model with Markov elements jointly described vincristine disposition and VIPN risk. Kenyan children showed lower clearance but markedly reduced PD sensitivity, resulting in negligible predicted VIPN even at higher doses. Incorporating informative censoring improved internal validity by capturing the observed dropout dynamics, while mechanistic extrapolation using CYP3A5, ABCB1, and CEP72 genotype distributions increased external validity and aligned model predictions better with empirical outcomes. Clinically, these findings support population\u2010specific vincristine dosing strategies and suggest that reduced neurotoxicity in African children reflects lower neuronal susceptibility rather than reduced systemic (plasma) exposure. Methodologically, this work demonstrates how unrecognized selection bias can distort PKPD extrapolations across populations and highlights the value of integrating mechanistic and genetic information within model\u2010based frameworks to improve the safety and external validity of model\u2010informed dosing strategies beyond the original study populations.<\/jats:p>","DOI":"10.1002\/psp4.70303","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T08:19:29Z","timestamp":1784535569000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Extrapolating Vincristine\u2010Induced Peripheral Neuropathy From Caucasian to Kenyan Populations: Impact of Type I and Type\n                    <scp>II<\/scp>\n                    Selection Bias"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6594-9813","authenticated-orcid":false,"given":"Maddalena","family":"Centanni","sequence":"first","affiliation":[{"name":"Department of Pharmacy Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjam Esther","family":"van de Velde","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology  Utrecht the Netherlands"},{"name":"Pediatric Oncology Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alwin D. 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Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1258-8297","authenticated-orcid":false,"given":"Mats O.","family":"Karlsson","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2979-679X","authenticated-orcid":false,"given":"Lena E.","family":"Friberg","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Uppsala University  Uppsala 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