Translation of Monoclonal Antibodies Pharmacokinetics from Animal to Human Using Physiologically Based Modeling in Open Systems Pharmacology (OSP) Suite: A Retrospective Analysis of Bevacizumab
Interspecies translation of monoclonal antibodies (mAbs) pharmacokinetics (PK) in presence of target-mediated drug disposition (TMDD) is particularly challenging. Incorporation of TMDD in physiologically based PK (PBPK) modeling is recent and needs to be consolidated and generalized to provide bette...
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| Format: | Article |
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MDPI AG
2023-08-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/8/2129 |
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| author | Blaise Pasquiers Salih Benamara Mathieu Felices David Ternant Xavier Declèves Alicja Puszkiel |
| author_facet | Blaise Pasquiers Salih Benamara Mathieu Felices David Ternant Xavier Declèves Alicja Puszkiel |
| author_sort | Blaise Pasquiers |
| collection | DOAJ |
| description | Interspecies translation of monoclonal antibodies (mAbs) pharmacokinetics (PK) in presence of target-mediated drug disposition (TMDD) is particularly challenging. Incorporation of TMDD in physiologically based PK (PBPK) modeling is recent and needs to be consolidated and generalized to provide better prediction of TMDD regarding inter-species translation during preclinical and clinical development steps of mAbs. The objective of this study was to develop a generic PBPK translational approach for mAbs using the open-source software (PK-Sim<sup>®</sup> and Mobi<sup>®</sup>). The translation of bevacizumab based on data in non-human primates (NHP), healthy volunteers (HV), and cancer patients was used as a case example for model demonstration purpose. A PBPK model for bevacizumab concentration-time data was developed using data from literature and the Open Systems Pharmacology (OSP) Suite version 10. PK-sim<sup>®</sup> was used to build the linear part of bevacizumab PK (mainly FcRn-mediated), whereas MoBi<sup>®</sup> was used to develop the target-mediated part. The model was first developed for NHP and used for a priori PK prediction in HV. Then, the refined model obtained in HV was used for a priori prediction in cancer patients. A priori predictions were within 2-fold prediction error (predicted/observed) for both area under the concentration-time curve (AUC) and maximum concentration (C<sub>max</sub>) and all the predicted concentrations were within 2-fold average fold error (AFE) and average absolute fold error (AAFE). Sensitivity analysis showed that FcRn-mediated distribution and elimination processes must be accounted for at all mAb concentration levels, whereas the lower the mAb concentration, the more significant the target-mediated elimination. This project is the first step to generalize the full PBPK translational approach in Model-Informed Drug Development (MIDD) of mAbs using OSP Suite. |
| first_indexed | 2024-03-10T23:39:43Z |
| format | Article |
| id | doaj.art-90f98f4a5788487281bfad7713e17aad |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T23:39:43Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-90f98f4a5788487281bfad7713e17aad2023-11-19T02:37:17ZengMDPI AGPharmaceutics1999-49232023-08-01158212910.3390/pharmaceutics15082129Translation of Monoclonal Antibodies Pharmacokinetics from Animal to Human Using Physiologically Based Modeling in Open Systems Pharmacology (OSP) Suite: A Retrospective Analysis of BevacizumabBlaise Pasquiers0Salih Benamara1Mathieu Felices2David Ternant3Xavier Declèves4Alicja Puszkiel5Inserm UMR-S1144, Faculty of Pharmacy, Université Paris Cité, 75006 Paris, FrancePhinC Development, 91300 Massy, FrancePhinC Development, 91300 Massy, FranceFaculty of Medicine, Université de Tours, EA 4245 T2I, 37032 Tours, FranceInserm UMR-S1144, Faculty of Pharmacy, Université Paris Cité, 75006 Paris, FranceInserm UMR-S1144, Faculty of Pharmacy, Université Paris Cité, 75006 Paris, FranceInterspecies translation of monoclonal antibodies (mAbs) pharmacokinetics (PK) in presence of target-mediated drug disposition (TMDD) is particularly challenging. Incorporation of TMDD in physiologically based PK (PBPK) modeling is recent and needs to be consolidated and generalized to provide better prediction of TMDD regarding inter-species translation during preclinical and clinical development steps of mAbs. The objective of this study was to develop a generic PBPK translational approach for mAbs using the open-source software (PK-Sim<sup>®</sup> and Mobi<sup>®</sup>). The translation of bevacizumab based on data in non-human primates (NHP), healthy volunteers (HV), and cancer patients was used as a case example for model demonstration purpose. A PBPK model for bevacizumab concentration-time data was developed using data from literature and the Open Systems Pharmacology (OSP) Suite version 10. PK-sim<sup>®</sup> was used to build the linear part of bevacizumab PK (mainly FcRn-mediated), whereas MoBi<sup>®</sup> was used to develop the target-mediated part. The model was first developed for NHP and used for a priori PK prediction in HV. Then, the refined model obtained in HV was used for a priori prediction in cancer patients. A priori predictions were within 2-fold prediction error (predicted/observed) for both area under the concentration-time curve (AUC) and maximum concentration (C<sub>max</sub>) and all the predicted concentrations were within 2-fold average fold error (AFE) and average absolute fold error (AAFE). Sensitivity analysis showed that FcRn-mediated distribution and elimination processes must be accounted for at all mAb concentration levels, whereas the lower the mAb concentration, the more significant the target-mediated elimination. This project is the first step to generalize the full PBPK translational approach in Model-Informed Drug Development (MIDD) of mAbs using OSP Suite.https://www.mdpi.com/1999-4923/15/8/2129translational PBPKmonoclonal antibodybevacizumabTMDD |
| spellingShingle | Blaise Pasquiers Salih Benamara Mathieu Felices David Ternant Xavier Declèves Alicja Puszkiel Translation of Monoclonal Antibodies Pharmacokinetics from Animal to Human Using Physiologically Based Modeling in Open Systems Pharmacology (OSP) Suite: A Retrospective Analysis of Bevacizumab Pharmaceutics translational PBPK monoclonal antibody bevacizumab TMDD |
| title | Translation of Monoclonal Antibodies Pharmacokinetics from Animal to Human Using Physiologically Based Modeling in Open Systems Pharmacology (OSP) Suite: A Retrospective Analysis of Bevacizumab |
| title_full | Translation of Monoclonal Antibodies Pharmacokinetics from Animal to Human Using Physiologically Based Modeling in Open Systems Pharmacology (OSP) Suite: A Retrospective Analysis of Bevacizumab |
| title_fullStr | Translation of Monoclonal Antibodies Pharmacokinetics from Animal to Human Using Physiologically Based Modeling in Open Systems Pharmacology (OSP) Suite: A Retrospective Analysis of Bevacizumab |
| title_full_unstemmed | Translation of Monoclonal Antibodies Pharmacokinetics from Animal to Human Using Physiologically Based Modeling in Open Systems Pharmacology (OSP) Suite: A Retrospective Analysis of Bevacizumab |
| title_short | Translation of Monoclonal Antibodies Pharmacokinetics from Animal to Human Using Physiologically Based Modeling in Open Systems Pharmacology (OSP) Suite: A Retrospective Analysis of Bevacizumab |
| title_sort | translation of monoclonal antibodies pharmacokinetics from animal to human using physiologically based modeling in open systems pharmacology osp suite a retrospective analysis of bevacizumab |
| topic | translational PBPK monoclonal antibody bevacizumab TMDD |
| url | https://www.mdpi.com/1999-4923/15/8/2129 |
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