{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T05:52:26Z","timestamp":1776664346210,"version":"3.51.2"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Physiological changes during pregnancy substantially alter opioid pharmacokinetics, yet clinical pharmacokinetic data in pregnant populations remain limited. Pharmacometric modeling using population pharmacokinetic (PopPK) and physiologically based pharmacokinetic (PBPK) approaches offers a quantitative framework to characterize these changes and to estimate maternal and fetal drug exposure. Despite increasing application of these methods, the methodological quality, reproducibility, and clinical relevance of existing opioid models in pregnancy have not been systematically evaluated. This systematic review aimed to critically appraise published PopPK and PBPK models of opioid medications in pregnancy, identify recurring structural and methodological features, and outline priorities for improving model development and reporting. A structured PubMed search (database inception to September 2025) identified studies modeling opioid disposition in pregnant individuals using PopPK or PBPK frameworks. Data on model structure, parameterization, assumptions, evaluation strategies, and reported limitations were extracted and synthesized. Ten studies met inclusion criteria, with fentanyl having the most studies. PopPK analyses consistently identified pregnancy as a significant covariate associated with increased clearance. PBPK models showed substantial heterogeneity in physiological detail, ranging from simplified fetoplacental compartments to permeability-limited placenta representations and multi-compartment fetal systems. Reproducibility emerged as a concern, with at least one PBPK model unable to be independently replicated due to incomplete reporting. Across studies, common gaps included limited verification datasets, incomplete representation of gestational physiology, and reliance on single-time-point umbilical cord concentrations at delivery. Overall, pharmacometric modeling provides valuable mechanistic insight into opioid disposition during pregnancy, but its translational impact is constrained by inconsistent reporting practices, sparse empirical data, and limited incorporation of fetal and neonatal exposure. Future progress will be accelerated by standardized documentation, improved pregnancy-specific physiological data, integration of genetic and developmental variability, and closer linkage between pharmacokinetics and clinically relevant outcomes to support model-informed perinatal opioid therapy.<\/jats:p>","DOI":"10.3389\/fphar.2026.1789714","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T05:23:37Z","timestamp":1776662617000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacometric modeling of opioid disposition in pregnancy: a systematic review of PopPK and PBPK approaches, model limitations, and future directions"],"prefix":"10.3389","volume":"17","author":[{"given":"Syed Saoud","family":"Zaidi","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine","place":["Indianapolis, IN, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad Yaseen","family":"Abbasi","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine","place":["Indianapolis, IN, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sruthi","family":"Ganapaneni","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine","place":["Indianapolis, IN, United States"]},{"name":"Creighton University School of Medicine \u2013 Phoenix","place":["Phoenix, AZ, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara K.","family":"Quinney","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine","place":["Indianapolis, IN, United States"]},{"name":"Department of Obstetrics and Gynecology, Indiana University School of Medicine","place":["Indianapolis, IN, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1007\/s10928-020-09711-2","article-title":"Prediction of maternal pharmacokinetics using physiologically based pharmacokinetic models: assessing the impact of the longitudinal changes in the activity of CYP1A2, CYP2D6 and CYP3A4 enzymes during pregnancy","volume":"47","author":"Abduljalil","year":"2020","journal-title":"J. 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