Mechanistic Coupling of a Novel in silico Cotyledon Perfusion Model and a Physiologically Based Pharmacokinetic Model to Predict Fetal Acetaminophen Pharmacokinetics at Delivery
Little is known about placental drug transfer and fetal pharmacokinetics despite increasing drug use in pregnant women. While physiologically based pharmacokinetic (PBPK) models can help in some cases to shed light on this knowledge gap, adequate parameterization of placental drug transfer remains c...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-09-01
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| Series: | Frontiers in Pediatrics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fped.2021.733520/full |
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| author | Paola Mian Bridget Nolan Bridget Nolan John N. van den Anker John N. van den Anker Kristel van Calsteren Kristel van Calsteren Karel Allegaert Karel Allegaert Karel Allegaert Nisha Lakhi Nisha Lakhi André Dallmann |
| author_facet | Paola Mian Bridget Nolan Bridget Nolan John N. van den Anker John N. van den Anker Kristel van Calsteren Kristel van Calsteren Karel Allegaert Karel Allegaert Karel Allegaert Nisha Lakhi Nisha Lakhi André Dallmann |
| author_sort | Paola Mian |
| collection | DOAJ |
| description | Little is known about placental drug transfer and fetal pharmacokinetics despite increasing drug use in pregnant women. While physiologically based pharmacokinetic (PBPK) models can help in some cases to shed light on this knowledge gap, adequate parameterization of placental drug transfer remains challenging. A novel in silico model with seven compartments representing the ex vivo cotyledon perfusion assay was developed and used to describe placental transfer and fetal pharmacokinetics of acetaminophen. Unknown parameters were optimized using observed data. Thereafter, values of relevant model parameters were copied to a maternal-fetal PBPK model and acetaminophen pharmacokinetics were predicted at delivery after oral administration of 1,000 mg. Predictions in the umbilical vein were evaluated with data from two clinical studies. Simulations from the in silico cotyledon perfusion model indicated that acetaminophen accumulates in the trophoblasts; simulated steady state concentrations in the trophoblasts were 4.31-fold higher than those in the perfusate. The whole-body PBPK model predicted umbilical vein concentrations with a mean prediction error of 24.7%. Of the 62 concentration values reported in the clinical studies, 50 values (81%) were predicted within a 2-fold error range. In conclusion, this study presents a novel in silico cotyledon perfusion model that is structurally congruent with the placenta implemented in our maternal-fetal PBPK model. This allows transferring parameters from the former model into our PBPK model for mechanistically exploring whole-body pharmacokinetics and concentration-effect relationships in the placental tissue. Further studies should investigate acetaminophen accumulation and metabolism in the placenta as the former might potentially affect placental prostaglandin synthesis and subsequent fetal exposure. |
| first_indexed | 2024-12-17T07:08:01Z |
| format | Article |
| id | doaj.art-8f68ce291dfd40d0b73ea8095533052a |
| institution | Directory Open Access Journal |
| issn | 2296-2360 |
| language | English |
| last_indexed | 2024-12-17T07:08:01Z |
| publishDate | 2021-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pediatrics |
| spelling | doaj.art-8f68ce291dfd40d0b73ea8095533052a2022-12-21T21:59:06ZengFrontiers Media S.A.Frontiers in Pediatrics2296-23602021-09-01910.3389/fped.2021.733520733520Mechanistic Coupling of a Novel in silico Cotyledon Perfusion Model and a Physiologically Based Pharmacokinetic Model to Predict Fetal Acetaminophen Pharmacokinetics at DeliveryPaola Mian0Bridget Nolan1Bridget Nolan2John N. van den Anker3John N. van den Anker4Kristel van Calsteren5Kristel van Calsteren6Karel Allegaert7Karel Allegaert8Karel Allegaert9Nisha Lakhi10Nisha Lakhi11André Dallmann12Department of Clinical Pharmacy, Medisch Spectrum Twente, Enschede, NetherlandsDepartment of Obstetrics and Gynecology, Richmond University Medical Center, Staten Island, NY, United StatesDepartment of Obstetrics and Gynecology, New York Medical College, Valhalla, NY, United StatesDivision of Clinical Pharmacology, Children's National Hospital, Washington, DC, United StatesDepartment of Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel, Basel, SwitzerlandDepartment of Development and Regeneration, KU Leuven, Leuven, BelgiumDepartment of Gynecology and Obstetrics, UZ Gasthuisberg, Leuven, BelgiumDepartment of Development and Regeneration, KU Leuven, Leuven, BelgiumDepartment of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, BelgiumDepartment of Hospital Pharmacy, Erasmus Medical Center Rotterdam, Rotterdam, NetherlandsDepartment of Obstetrics and Gynecology, Richmond University Medical Center, Staten Island, NY, United StatesDepartment of Obstetrics and Gynecology, New York Medical College, Valhalla, NY, United States0Pharmacometrics/Modeling and Simulation, Research and Development, Pharmaceuticals, Bayer AG, Leverkusen, GermanyLittle is known about placental drug transfer and fetal pharmacokinetics despite increasing drug use in pregnant women. While physiologically based pharmacokinetic (PBPK) models can help in some cases to shed light on this knowledge gap, adequate parameterization of placental drug transfer remains challenging. A novel in silico model with seven compartments representing the ex vivo cotyledon perfusion assay was developed and used to describe placental transfer and fetal pharmacokinetics of acetaminophen. Unknown parameters were optimized using observed data. Thereafter, values of relevant model parameters were copied to a maternal-fetal PBPK model and acetaminophen pharmacokinetics were predicted at delivery after oral administration of 1,000 mg. Predictions in the umbilical vein were evaluated with data from two clinical studies. Simulations from the in silico cotyledon perfusion model indicated that acetaminophen accumulates in the trophoblasts; simulated steady state concentrations in the trophoblasts were 4.31-fold higher than those in the perfusate. The whole-body PBPK model predicted umbilical vein concentrations with a mean prediction error of 24.7%. Of the 62 concentration values reported in the clinical studies, 50 values (81%) were predicted within a 2-fold error range. In conclusion, this study presents a novel in silico cotyledon perfusion model that is structurally congruent with the placenta implemented in our maternal-fetal PBPK model. This allows transferring parameters from the former model into our PBPK model for mechanistically exploring whole-body pharmacokinetics and concentration-effect relationships in the placental tissue. Further studies should investigate acetaminophen accumulation and metabolism in the placenta as the former might potentially affect placental prostaglandin synthesis and subsequent fetal exposure.https://www.frontiersin.org/articles/10.3389/fped.2021.733520/fullacetaminophenex vivo cotyledon perfusionphysiologically-based pharmacokineticsplacental transfermaternal-fetalpregnancy |
| spellingShingle | Paola Mian Bridget Nolan Bridget Nolan John N. van den Anker John N. van den Anker Kristel van Calsteren Kristel van Calsteren Karel Allegaert Karel Allegaert Karel Allegaert Nisha Lakhi Nisha Lakhi André Dallmann Mechanistic Coupling of a Novel in silico Cotyledon Perfusion Model and a Physiologically Based Pharmacokinetic Model to Predict Fetal Acetaminophen Pharmacokinetics at Delivery Frontiers in Pediatrics acetaminophen ex vivo cotyledon perfusion physiologically-based pharmacokinetics placental transfer maternal-fetal pregnancy |
| title | Mechanistic Coupling of a Novel in silico Cotyledon Perfusion Model and a Physiologically Based Pharmacokinetic Model to Predict Fetal Acetaminophen Pharmacokinetics at Delivery |
| title_full | Mechanistic Coupling of a Novel in silico Cotyledon Perfusion Model and a Physiologically Based Pharmacokinetic Model to Predict Fetal Acetaminophen Pharmacokinetics at Delivery |
| title_fullStr | Mechanistic Coupling of a Novel in silico Cotyledon Perfusion Model and a Physiologically Based Pharmacokinetic Model to Predict Fetal Acetaminophen Pharmacokinetics at Delivery |
| title_full_unstemmed | Mechanistic Coupling of a Novel in silico Cotyledon Perfusion Model and a Physiologically Based Pharmacokinetic Model to Predict Fetal Acetaminophen Pharmacokinetics at Delivery |
| title_short | Mechanistic Coupling of a Novel in silico Cotyledon Perfusion Model and a Physiologically Based Pharmacokinetic Model to Predict Fetal Acetaminophen Pharmacokinetics at Delivery |
| title_sort | mechanistic coupling of a novel in silico cotyledon perfusion model and a physiologically based pharmacokinetic model to predict fetal acetaminophen pharmacokinetics at delivery |
| topic | acetaminophen ex vivo cotyledon perfusion physiologically-based pharmacokinetics placental transfer maternal-fetal pregnancy |
| url | https://www.frontiersin.org/articles/10.3389/fped.2021.733520/full |
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