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Recommendations were made for the oral dose of tramadol to be used in a prospective study in children (3\u00a0months to &lt; 18\u2009years old) with chronic pain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Intravenous pharmacokinetic and genotype data from neonatal patients (<jats:italic>n<\/jats:italic>\u2009=\u200946) were available for this analysis. The time course of tramadol and O\u2010desmethyltramadol (M1) concentrations was characterized using a nonlinear mixed effects approach in conjunction with extrapolation principles. Clinical trial simulations were then implemented to explore the effects of polymorphism, maturation and developmental growth on the disposition of tramadol and M1. Reported efficacious exposure range in adult subjects were used as reference.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The pharmacokinetics of tramadol and M1 was characterized by a two\u2010compartment model. The total clearance of tramadol (CLPP) comprised CYP2D6\u2010mediated metabolism (CLPM) and other pathways (CLPO). Age\u2010related changes in CLPM, CLPO and M1 clearance (CLMO) were described by a sigmoid function, with CYP2D6 as a covariate on CLPP and CLPM, \u00a0and OCT1 on CLMO. Simulation scenarios including\u00a0different CYP2D6\/OCT1 combinations revealed that steady\u2010state concentrations are above the putative ranges for analgesia in &gt;15% and &gt;70% of subjects after doses of 3 and 8\u00a0mg\/kg, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In the absence of genotyping, reference exposure ranges can be used to define the dose rationale for tramadol in paediatric chronic pain. However, a starting dose of 0.5\u00a0mg\/kg\/day should be considered, followed by stepwise titration to the desired analgesic response.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.16201","type":"journal-article","created":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T14:14:10Z","timestamp":1728569650000},"page":"283-296","source":"Crossref","is-referenced-by-count":7,"title":["Evaluation of the effect of CYP2D6 and OCT1 polymorphisms on the pharmacokinetics of tramadol: Implications for clinical safety and dose rationale in paediatric chronic pain"],"prefix":"10.1111","volume":"91","author":[{"given":"Paul","family":"Healy","sequence":"first","affiliation":[{"name":"Clinical Pharmacology &amp; Therapeutics Group University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karel","family":"Allegaert","sequence":"additional","affiliation":[{"name":"Department of Development and Regeneration KU Leuven  Leuven Belgium"},{"name":"Department of Pharmaceutical and Pharmacological Sciences KU Leuven  Leuven Belgium"},{"name":"Department of Hospital Pharmacy Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6211-1430","authenticated-orcid":false,"given":"Oscar","family":"Della Pasqua","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology &amp; Therapeutics Group University College London  London UK"},{"name":"Clinical Pharmacology Modelling and Simulation GlaxoSmithKline  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,10,9]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0000000000000057"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003495\u2010199346020\u201000008"},{"key":"e_1_2_9_4_1","volume-title":"Drug safety communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women","author":"Food and Drug Administration"},{"key":"e_1_2_9_5_1","volume-title":"Pharmacovigilance risk assessment committee. 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