Physiologically based mechanistic insight into differential risk of valproate hepatotoxicity between children and adults: A focus on ontogeny impact
Abstract The anticonvulsant valproic acid (VPA) despite complex pharmacokinetics has been in clinical use for nearly 6 decades. Previous reports indicated neonates, infants, and toddlers/preschoolers had higher risk of valproate hepatotoxicity than adults. However, dosing recommendations for those l...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-12-01
|
| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.13045 |
| _version_ | 1797388943881142272 |
|---|---|
| author | Yu‐Ting Huang Yen‐Ming Huang Fan‐Lu Kung Chun‐Jung Lin Tun Jao Yunn‐Fang Ho |
| author_facet | Yu‐Ting Huang Yen‐Ming Huang Fan‐Lu Kung Chun‐Jung Lin Tun Jao Yunn‐Fang Ho |
| author_sort | Yu‐Ting Huang |
| collection | DOAJ |
| description | Abstract The anticonvulsant valproic acid (VPA) despite complex pharmacokinetics has been in clinical use for nearly 6 decades. Previous reports indicated neonates, infants, and toddlers/preschoolers had higher risk of valproate hepatotoxicity than adults. However, dosing recommendations for those less than 10 years of age are lacking. To decipher clinical puzzles, physiologically‐based pharmacokinetic (PBPK) models of VPA and its hepatotoxic metabolite 4‐ene‐VPA were constructed and simulated with particularly integrated information of drug‐metabolizing enzyme ontogeny. Adult and pediatric PK data of VPA (n = 143 subjects) and 4‐ene‐VPA (n = 8 subjects) collected from previous reports were used for model development and validation. Sensitivity analyses were performed to characterize ontogeny impacts of CYP2C9 and UGT2B7 on dispositions of VPA and 4‐ene‐VPA across age groups. Optimal VPA dosing for each pediatric age group was also predicted and objectively judged by ensuring VPA efficacy and avoiding 4‐ene‐VPA hepatotoxicity. The study revealed UGT2B7 ontogeny was quite influential on VPA clearance even in neonates and small children. Intrinsic clearance of CYP2C9 was the most prominent determinant for areas under the concentration‐time curve of VPA and 4‐ene‐VPA in infants, and toddlers/preschoolers, reflecting higher hepatotoxicity risk due to noxious 4‐ene‐VPA accumulation in these groups. The ontogeny‐based PBPK approach complements conventional allometric methods in dosing estimation for the young by providing more mechanistic insight of the processes changing with age. The established ontogeny‐based PBPK approach for VPA therapy deserves further corroboration by real‐world therapeutic data to affirm its clinical applicability. |
| first_indexed | 2024-03-08T22:48:17Z |
| format | Article |
| id | doaj.art-7d2a97493e2f42c1852e6b1e24f3f99a |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-03-08T22:48:17Z |
| publishDate | 2023-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-7d2a97493e2f42c1852e6b1e24f3f99a2023-12-16T18:59:25ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062023-12-0112121960197110.1002/psp4.13045Physiologically based mechanistic insight into differential risk of valproate hepatotoxicity between children and adults: A focus on ontogeny impactYu‐Ting Huang0Yen‐Ming Huang1Fan‐Lu Kung2Chun‐Jung Lin3Tun Jao4Yunn‐Fang Ho5School of Pharmacy, College of Medicine National Taiwan University Taipei TaiwanSchool of Pharmacy, College of Medicine National Taiwan University Taipei TaiwanSchool of Pharmacy, College of Medicine National Taiwan University Taipei TaiwanSchool of Pharmacy, College of Medicine National Taiwan University Taipei TaiwanDepartment of Neurology National Taiwan University Hospital Taipei TaiwanSchool of Pharmacy, College of Medicine National Taiwan University Taipei TaiwanAbstract The anticonvulsant valproic acid (VPA) despite complex pharmacokinetics has been in clinical use for nearly 6 decades. Previous reports indicated neonates, infants, and toddlers/preschoolers had higher risk of valproate hepatotoxicity than adults. However, dosing recommendations for those less than 10 years of age are lacking. To decipher clinical puzzles, physiologically‐based pharmacokinetic (PBPK) models of VPA and its hepatotoxic metabolite 4‐ene‐VPA were constructed and simulated with particularly integrated information of drug‐metabolizing enzyme ontogeny. Adult and pediatric PK data of VPA (n = 143 subjects) and 4‐ene‐VPA (n = 8 subjects) collected from previous reports were used for model development and validation. Sensitivity analyses were performed to characterize ontogeny impacts of CYP2C9 and UGT2B7 on dispositions of VPA and 4‐ene‐VPA across age groups. Optimal VPA dosing for each pediatric age group was also predicted and objectively judged by ensuring VPA efficacy and avoiding 4‐ene‐VPA hepatotoxicity. The study revealed UGT2B7 ontogeny was quite influential on VPA clearance even in neonates and small children. Intrinsic clearance of CYP2C9 was the most prominent determinant for areas under the concentration‐time curve of VPA and 4‐ene‐VPA in infants, and toddlers/preschoolers, reflecting higher hepatotoxicity risk due to noxious 4‐ene‐VPA accumulation in these groups. The ontogeny‐based PBPK approach complements conventional allometric methods in dosing estimation for the young by providing more mechanistic insight of the processes changing with age. The established ontogeny‐based PBPK approach for VPA therapy deserves further corroboration by real‐world therapeutic data to affirm its clinical applicability.https://doi.org/10.1002/psp4.13045 |
| spellingShingle | Yu‐Ting Huang Yen‐Ming Huang Fan‐Lu Kung Chun‐Jung Lin Tun Jao Yunn‐Fang Ho Physiologically based mechanistic insight into differential risk of valproate hepatotoxicity between children and adults: A focus on ontogeny impact CPT: Pharmacometrics & Systems Pharmacology |
| title | Physiologically based mechanistic insight into differential risk of valproate hepatotoxicity between children and adults: A focus on ontogeny impact |
| title_full | Physiologically based mechanistic insight into differential risk of valproate hepatotoxicity between children and adults: A focus on ontogeny impact |
| title_fullStr | Physiologically based mechanistic insight into differential risk of valproate hepatotoxicity between children and adults: A focus on ontogeny impact |
| title_full_unstemmed | Physiologically based mechanistic insight into differential risk of valproate hepatotoxicity between children and adults: A focus on ontogeny impact |
| title_short | Physiologically based mechanistic insight into differential risk of valproate hepatotoxicity between children and adults: A focus on ontogeny impact |
| title_sort | physiologically based mechanistic insight into differential risk of valproate hepatotoxicity between children and adults a focus on ontogeny impact |
| url | https://doi.org/10.1002/psp4.13045 |
| work_keys_str_mv | AT yutinghuang physiologicallybasedmechanisticinsightintodifferentialriskofvalproatehepatotoxicitybetweenchildrenandadultsafocusonontogenyimpact AT yenminghuang physiologicallybasedmechanisticinsightintodifferentialriskofvalproatehepatotoxicitybetweenchildrenandadultsafocusonontogenyimpact AT fanlukung physiologicallybasedmechanisticinsightintodifferentialriskofvalproatehepatotoxicitybetweenchildrenandadultsafocusonontogenyimpact AT chunjunglin physiologicallybasedmechanisticinsightintodifferentialriskofvalproatehepatotoxicitybetweenchildrenandadultsafocusonontogenyimpact AT tunjao physiologicallybasedmechanisticinsightintodifferentialriskofvalproatehepatotoxicitybetweenchildrenandadultsafocusonontogenyimpact AT yunnfangho physiologicallybasedmechanisticinsightintodifferentialriskofvalproatehepatotoxicitybetweenchildrenandadultsafocusonontogenyimpact |