145: Physiologically-based Pharmacokinetic Models of Opioid in Pregnancy, Maternal-Fetal, Pediatrics & Breastfeeding Mothers: A Systematic Literature Review

Statement of Purpose, Innovation or Hypothesis: Physiologically-based pharmacokinetic (PBPK) modeling is commonly used to support the extrapolation of adult data to pregnant and pediatric populations. The Maternal and Pediatric Precision in Therapeutics (MPRINT) Hub Knowledgebase aggregates resources relating to pharmacokinetics and pharmacodynamics of medications in maternal and pediatric populations. As part of this effort, this study aimed to comprehensively review and curate published PBPK models for opioids in pregnant, lactating, and pediatric populations. Our objectives included identifying existing research gaps relating to opioid PBPK within these populations, proposing best practices for the publication of the PBPK model, and advancing the development of the MPRINT Knowledgebase.

Description of Methods & Materials: PubMed was searched from inception through April 2024, utilizing a comprehensive set of search terms including each of 30 opioid drug names AND (“PBPK”) AND (“pregnan”, OR “Obstet”, OR OR “matern, OR“mother” , OR “lactat”,  OR “pediatric”, OR “child”, OR “neonat”, OR “baby”, OR “adolsec”, OR“ preterm”, OR “infant”). Articles meeting inclusion criteria provided clinical data, featured PBPK modeling in pregnant, lactating, or pediatric populations, and were written in English. Data relating to the modeling software, structure and methodology used, study population, study objectives, validation criteria, and other pertinent information were manually extracted.

Data & Results: After a full-text review, 29 research papers published between 2006-2024 were identified as using PBPK models to describe opioid PK in the maternal or pediatric population. The majority of studies (n=22) focused on pediatric patients with 13 models including children under the age of 2 years.  Seven studies focused on pregnancy. No PBPK models of opioids in lactation were identified.  Buprenorphine (n=6), methadone (n=5), and morphine (n=4) were the most frequently studied drugs, followed by tramadol and sufentanil (n=3), alfentanil, oxycodone, and fentanyl (n=2). Simcyp (n=16) was the most commonly used software. If validation criteria were reported, it was usually 0.5 to 2-fold (n=9). A limited number of studies incorporated permeability-based distribution models and evaluated the role of transporters, p-glycoprotein, and OATP1B1.

Interpretation, Conclusion or Significance: Several PBPK models of opioids in pregnancy or pediatrics have been reported, the majority utilizing Simcyp software.  Buprenorphine, methadone, and morphine are most frequently studied, likely due to their use to treat opioid use disorder in pregnancy and neonatal opioid withdrawal. PBPK models in pregnant or pediatric populations have been developed for only 8 of the 30 opioid medications included in the search, and no PBPK models of opioids in lactation were identified, indicating gaps in maternal and pediatric pharmacology research

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