{"title":"Clinical validation of translational antibody PBPK model using tissue distribution data generated with <sup>89</sup>Zr-immuno-PET imaging.","authors":"Shufang Liu, Zhe Li, Marc Huisman, Dhaval K Shah","doi":"10.1007/s10928-023-09869-5","DOIUrl":null,"url":null,"abstract":"<p><p>The main objective of this manuscript was to validate the ability of the monoclonal antibody physiologically-based pharmacokinetic (PBPK) model to predict tissue concentrations of antibodies in the human. To accomplish this goal, preclinical and clinical tissue distribution and positron emission tomography imaging data generated using zirconium-89 (<sup>89</sup>Zr) labeled antibodies were obtained from the literature. First, our previously published translational PBPK model for antibodies was expanded to describe the whole-body biodistribution of <sup>89</sup>Zr labeled antibody and the free <sup>89</sup>Zr, as well as residualization of free <sup>89</sup>Zr. Subsequently, the model was optimized using mouse biodistribution data, where it was observed that free <sup>89</sup>Zr mainly residualizes in the bone and the extent of antibody distribution in certain tissues (e.g., liver and spleen) may be altered by labeling with <sup>89</sup>Zr. The mouse PBPK model was scaled to rat, monkey, and human by simply changing the physiological parameters, and a priori simulations performed by the model were compared with the observed PK data. It was found that model predicted antibody PK in majority of the tissues in all the species superimposed over the observed data, and the model was also able to predict the PK of antibody in human tissues reasonably well. As such, the work presented here provides unprecedented evaluation of the antibody PPBK model for its ability to predict tissue PK of antibodies in the clinic. This model can be used for preclinical-to-clinical translation of antibodies and for prediction of antibody concentrations at the site-of-action in the clinic.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"50 5","pages":"377-394"},"PeriodicalIF":2.2000,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Pharmacokinetics and Pharmacodynamics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10928-023-09869-5","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/6/29 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
The main objective of this manuscript was to validate the ability of the monoclonal antibody physiologically-based pharmacokinetic (PBPK) model to predict tissue concentrations of antibodies in the human. To accomplish this goal, preclinical and clinical tissue distribution and positron emission tomography imaging data generated using zirconium-89 (89Zr) labeled antibodies were obtained from the literature. First, our previously published translational PBPK model for antibodies was expanded to describe the whole-body biodistribution of 89Zr labeled antibody and the free 89Zr, as well as residualization of free 89Zr. Subsequently, the model was optimized using mouse biodistribution data, where it was observed that free 89Zr mainly residualizes in the bone and the extent of antibody distribution in certain tissues (e.g., liver and spleen) may be altered by labeling with 89Zr. The mouse PBPK model was scaled to rat, monkey, and human by simply changing the physiological parameters, and a priori simulations performed by the model were compared with the observed PK data. It was found that model predicted antibody PK in majority of the tissues in all the species superimposed over the observed data, and the model was also able to predict the PK of antibody in human tissues reasonably well. As such, the work presented here provides unprecedented evaluation of the antibody PPBK model for its ability to predict tissue PK of antibodies in the clinic. This model can be used for preclinical-to-clinical translation of antibodies and for prediction of antibody concentrations at the site-of-action in the clinic.
期刊介绍:
Broadly speaking, the Journal of Pharmacokinetics and Pharmacodynamics covers the area of pharmacometrics. The journal is devoted to illustrating the importance of pharmacokinetics, pharmacodynamics, and pharmacometrics in drug development, clinical care, and the understanding of drug action. The journal publishes on a variety of topics related to pharmacometrics, including, but not limited to, clinical, experimental, and theoretical papers examining the kinetics of drug disposition and effects of drug action in humans, animals, in vitro, or in silico; modeling and simulation methodology, including optimal design; precision medicine; systems pharmacology; and mathematical pharmacology (including computational biology, bioengineering, and biophysics related to pharmacology, pharmacokinetics, orpharmacodynamics). Clinical papers that include population pharmacokinetic-pharmacodynamic relationships are welcome. The journal actively invites and promotes up-and-coming areas of pharmacometric research, such as real-world evidence, quality of life analyses, and artificial intelligence. The Journal of Pharmacokinetics and Pharmacodynamics is an official journal of the International Society of Pharmacometrics.