Marjolein D van Borselen, Laurens Auke Æmiel Sluijterman, Rick Greupink, Saskia N de Wildt
{"title":"对基于生理学的药代动力学模型的预测性能进行更稳健的评估:使用置信区间支持在临床护理中使用模型指导用药。","authors":"Marjolein D van Borselen, Laurens Auke Æmiel Sluijterman, Rick Greupink, Saskia N de Wildt","doi":"10.1007/s40262-023-01326-3","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objective: </strong>With the rise in the use of physiologically based pharmacokinetic (PBPK) modeling over the past decade, the use of PBPK modeling to underpin drug dosing for off-label use in clinical care has become an attractive option. In order to use PBPK models for high-impact decisions, thorough qualification and validation of the model is essential to gain enough confidence in model performance. Currently, there is no agreed method for model acceptance, while clinicians demand a clear measure of model performance before considering implementing PBPK model-informed dosing. We aim to bridge this gap and propose the use of a confidence interval for the predicted-to-observed geometric mean ratio with predefined boundaries. This approach is similar to currently accepted bioequivalence testing procedures and can aid in improved model credibility and acceptance.</p><p><strong>Methods: </strong>Two different methods to construct a confidence interval are outlined, depending on whether individual observations or aggregate data are available from the clinical comparator data sets. The two testing procedures are demonstrated for an example evaluation of a midazolam PBPK model. In addition, a simulation study is performed to demonstrate the difference between the twofold criterion and our proposed method.</p><p><strong>Results: </strong>Using midazolam adult pharmacokinetic data, we demonstrated that creating a confidence interval yields more robust evaluation of the model than a point estimate, such as the commonly used twofold acceptance criterion. Additionally, we showed that the use of individual predictions can reduce the number of required test subjects. Furthermore, an easy-to-implement software tool was developed and is provided to make our proposed method more accessible.</p><p><strong>Conclusions: </strong>With this method, we aim to provide a tool to further increase confidence in PBPK model performance and facilitate its use for directly informing drug dosing in clinical care.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.6000,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10954928/pdf/","citationCount":"0","resultStr":"{\"title\":\"Towards More Robust Evaluation of the Predictive Performance of Physiologically Based Pharmacokinetic Models: Using Confidence Intervals to Support Use of Model-Informed Dosing in Clinical Care.\",\"authors\":\"Marjolein D van Borselen, Laurens Auke Æmiel Sluijterman, Rick Greupink, Saskia N de Wildt\",\"doi\":\"10.1007/s40262-023-01326-3\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objective: </strong>With the rise in the use of physiologically based pharmacokinetic (PBPK) modeling over the past decade, the use of PBPK modeling to underpin drug dosing for off-label use in clinical care has become an attractive option. In order to use PBPK models for high-impact decisions, thorough qualification and validation of the model is essential to gain enough confidence in model performance. Currently, there is no agreed method for model acceptance, while clinicians demand a clear measure of model performance before considering implementing PBPK model-informed dosing. We aim to bridge this gap and propose the use of a confidence interval for the predicted-to-observed geometric mean ratio with predefined boundaries. This approach is similar to currently accepted bioequivalence testing procedures and can aid in improved model credibility and acceptance.</p><p><strong>Methods: </strong>Two different methods to construct a confidence interval are outlined, depending on whether individual observations or aggregate data are available from the clinical comparator data sets. The two testing procedures are demonstrated for an example evaluation of a midazolam PBPK model. In addition, a simulation study is performed to demonstrate the difference between the twofold criterion and our proposed method.</p><p><strong>Results: </strong>Using midazolam adult pharmacokinetic data, we demonstrated that creating a confidence interval yields more robust evaluation of the model than a point estimate, such as the commonly used twofold acceptance criterion. Additionally, we showed that the use of individual predictions can reduce the number of required test subjects. Furthermore, an easy-to-implement software tool was developed and is provided to make our proposed method more accessible.</p><p><strong>Conclusions: </strong>With this method, we aim to provide a tool to further increase confidence in PBPK model performance and facilitate its use for directly informing drug dosing in clinical care.</p>\",\"PeriodicalId\":10405,\"journal\":{\"name\":\"Clinical Pharmacokinetics\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2024-03-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10954928/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Pharmacokinetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s40262-023-01326-3\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/2/15 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/s40262-023-01326-3","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/2/15 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Towards More Robust Evaluation of the Predictive Performance of Physiologically Based Pharmacokinetic Models: Using Confidence Intervals to Support Use of Model-Informed Dosing in Clinical Care.
Background and objective: With the rise in the use of physiologically based pharmacokinetic (PBPK) modeling over the past decade, the use of PBPK modeling to underpin drug dosing for off-label use in clinical care has become an attractive option. In order to use PBPK models for high-impact decisions, thorough qualification and validation of the model is essential to gain enough confidence in model performance. Currently, there is no agreed method for model acceptance, while clinicians demand a clear measure of model performance before considering implementing PBPK model-informed dosing. We aim to bridge this gap and propose the use of a confidence interval for the predicted-to-observed geometric mean ratio with predefined boundaries. This approach is similar to currently accepted bioequivalence testing procedures and can aid in improved model credibility and acceptance.
Methods: Two different methods to construct a confidence interval are outlined, depending on whether individual observations or aggregate data are available from the clinical comparator data sets. The two testing procedures are demonstrated for an example evaluation of a midazolam PBPK model. In addition, a simulation study is performed to demonstrate the difference between the twofold criterion and our proposed method.
Results: Using midazolam adult pharmacokinetic data, we demonstrated that creating a confidence interval yields more robust evaluation of the model than a point estimate, such as the commonly used twofold acceptance criterion. Additionally, we showed that the use of individual predictions can reduce the number of required test subjects. Furthermore, an easy-to-implement software tool was developed and is provided to make our proposed method more accessible.
Conclusions: With this method, we aim to provide a tool to further increase confidence in PBPK model performance and facilitate its use for directly informing drug dosing in clinical care.
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.