Eleni Karatza, Jaydeep Sinha, Patricia D Maglalang, Andrea Edginton, Daniel Gonzalez
{"title":"基于生理学的总和未结合丙戊酸药代动力学模型,用于评估低白蛋白血症和无低白蛋白血症儿童的用药剂量。","authors":"Eleni Karatza, Jaydeep Sinha, Patricia D Maglalang, Andrea Edginton, Daniel Gonzalez","doi":"10.1007/s40262-024-01418-8","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objective: </strong>Valproic acid (VPA) demonstrates nonlinear pharmacokinetics (PK) due to a capacity-limited protein binding, which has potential implications on its total and unbound plasma concentrations, especially during hypoalbuminemia. A physiologically based pharmacokinetic (PBPK) model was developed to assess the nonlinear dose-exposure relationship of VPA with special emphasis on pediatric patients with hypoalbuminemia.</p><p><strong>Methods: </strong>A PBPK model was first developed and evaluated in adults using PK-Sim<sup>®</sup> and MoBi<sup>®</sup> (v.11) and the scaled to children 1 year and older. The capacity-limited protein binding was characterized by second-order kinetics between VPA and albumin with a 2:1 molar ratio. All drug-specific parameters were informed by literature and optimized using published PK data of VPA. PK simulations were performed in virtual populations with normal and low albumin levels.</p><p><strong>Results: </strong>The reported concentration-time profiles of total and unbound VPA were adequately predicted by the PBPK model across the age and dose range (3-120 mg/kg). The model was able to characterize the nonlinear PK, as the concentration-dependent fraction unbound (f<sub>u</sub>) and the related dose-dependent clearance values were well predicted. Simulated steady-state trough concentrations of total VPA were less than dose-proportional and were within the therapeutic drug monitoring range of 50-100 mg/L for doses between 30 and 45 mg/kg per day in children with normal albumin concentrations. However, virtual children with hypoalbuminemia largely failed to achieve the target exposure.</p><p><strong>Conclusion: </strong>The PBPK model helped assess the nonlinear dose-exposure relationship of VPA and the impact of albumin concentrations on the achievement of target exposure.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1435-1448"},"PeriodicalIF":4.6000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11521762/pdf/","citationCount":"0","resultStr":"{\"title\":\"Physiologically-Based Pharmacokinetic Modeling of Total and Unbound Valproic Acid to Evaluate Dosing in Children With and Without Hypoalbuminemia.\",\"authors\":\"Eleni Karatza, Jaydeep Sinha, Patricia D Maglalang, Andrea Edginton, Daniel Gonzalez\",\"doi\":\"10.1007/s40262-024-01418-8\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objective: </strong>Valproic acid (VPA) demonstrates nonlinear pharmacokinetics (PK) due to a capacity-limited protein binding, which has potential implications on its total and unbound plasma concentrations, especially during hypoalbuminemia. A physiologically based pharmacokinetic (PBPK) model was developed to assess the nonlinear dose-exposure relationship of VPA with special emphasis on pediatric patients with hypoalbuminemia.</p><p><strong>Methods: </strong>A PBPK model was first developed and evaluated in adults using PK-Sim<sup>®</sup> and MoBi<sup>®</sup> (v.11) and the scaled to children 1 year and older. The capacity-limited protein binding was characterized by second-order kinetics between VPA and albumin with a 2:1 molar ratio. All drug-specific parameters were informed by literature and optimized using published PK data of VPA. PK simulations were performed in virtual populations with normal and low albumin levels.</p><p><strong>Results: </strong>The reported concentration-time profiles of total and unbound VPA were adequately predicted by the PBPK model across the age and dose range (3-120 mg/kg). The model was able to characterize the nonlinear PK, as the concentration-dependent fraction unbound (f<sub>u</sub>) and the related dose-dependent clearance values were well predicted. Simulated steady-state trough concentrations of total VPA were less than dose-proportional and were within the therapeutic drug monitoring range of 50-100 mg/L for doses between 30 and 45 mg/kg per day in children with normal albumin concentrations. However, virtual children with hypoalbuminemia largely failed to achieve the target exposure.</p><p><strong>Conclusion: </strong>The PBPK model helped assess the nonlinear dose-exposure relationship of VPA and the impact of albumin concentrations on the achievement of target exposure.</p>\",\"PeriodicalId\":10405,\"journal\":{\"name\":\"Clinical Pharmacokinetics\",\"volume\":\" \",\"pages\":\"1435-1448\"},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2024-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11521762/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Pharmacokinetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s40262-024-01418-8\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/9/19 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Pharmacokinetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s40262-024-01418-8","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/19 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Physiologically-Based Pharmacokinetic Modeling of Total and Unbound Valproic Acid to Evaluate Dosing in Children With and Without Hypoalbuminemia.
Background and objective: Valproic acid (VPA) demonstrates nonlinear pharmacokinetics (PK) due to a capacity-limited protein binding, which has potential implications on its total and unbound plasma concentrations, especially during hypoalbuminemia. A physiologically based pharmacokinetic (PBPK) model was developed to assess the nonlinear dose-exposure relationship of VPA with special emphasis on pediatric patients with hypoalbuminemia.
Methods: A PBPK model was first developed and evaluated in adults using PK-Sim® and MoBi® (v.11) and the scaled to children 1 year and older. The capacity-limited protein binding was characterized by second-order kinetics between VPA and albumin with a 2:1 molar ratio. All drug-specific parameters were informed by literature and optimized using published PK data of VPA. PK simulations were performed in virtual populations with normal and low albumin levels.
Results: The reported concentration-time profiles of total and unbound VPA were adequately predicted by the PBPK model across the age and dose range (3-120 mg/kg). The model was able to characterize the nonlinear PK, as the concentration-dependent fraction unbound (fu) and the related dose-dependent clearance values were well predicted. Simulated steady-state trough concentrations of total VPA were less than dose-proportional and were within the therapeutic drug monitoring range of 50-100 mg/L for doses between 30 and 45 mg/kg per day in children with normal albumin concentrations. However, virtual children with hypoalbuminemia largely failed to achieve the target exposure.
Conclusion: The PBPK model helped assess the nonlinear dose-exposure relationship of VPA and the impact of albumin concentrations on the achievement of target exposure.
期刊介绍:
Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics.
Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.