Physiologically Based Pharmacokinetic Models for Infliximab, Ipilimumab, and Nivolumab Developed with GastroPlus to Predict Hepatic Concentrations
<b>Background/Objectives:</b> Infliximab, ipilimumab, and nivolumab are three monoclonal antibodies that have been associated with hepatotoxicity. Three separate physiologically based pharmacokinetic (PBPK) models were developed in GastroPlus<sup>®</sup> to simulate plasma an...
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2025-03-01
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| Online Access: | https://www.mdpi.com/1999-4923/17/3/372 |
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| author | Celeste Vallejo Cameron Meaney Lara Clemens Kyunghee Yang Viera Lukacova Haiying Zhou |
| author_facet | Celeste Vallejo Cameron Meaney Lara Clemens Kyunghee Yang Viera Lukacova Haiying Zhou |
| author_sort | Celeste Vallejo |
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| description | <b>Background/Objectives:</b> Infliximab, ipilimumab, and nivolumab are three monoclonal antibodies that have been associated with hepatotoxicity. Three separate physiologically based pharmacokinetic (PBPK) models were developed in GastroPlus<sup>®</sup> to simulate plasma and liver concentrations in patient populations after administration of either infliximab, ipilimumab, or nivolumab. <b>Methods:</b> The models include distribution and clearance mechanisms specific to large molecules, FcRn binding dynamics, and target-mediated drug disposition (TNF-α for infliximab, CTLA-4 for ipilimumab, and PD-1 for nivolumab). <b>Results:</b> The PBPK model for each large molecule was able to reproduce observed plasma concentration data in patient populations, including patients with rheumatoid arthritis and patients with solid tumors. Liver concentrations were predicted to be between 10% and 23% of the plasma concentrations for each of the three drugs, aligning with previously reported results. This lends further validity to the PBPK models and their ability to accurately predict hepatic concentrations in the absence of direct tissue measurements. <b>Conclusions:</b> These results can be used to drive liver toxicity predictions using the quantitative systems toxicology model, BIOLOGXsym™, which integrates hepatic interstitial concentrations with in vitro mechanistic toxicity data to predict the extent of liver toxicity for biologics. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-03-01 |
| publisher | MDPI AG |
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| series | Pharmaceutics |
| spelling | doaj-art-3ef8970a7a4741bf9f6c7d2e7da9e05c2025-08-20T03:43:34ZengMDPI AGPharmaceutics1999-49232025-03-0117337210.3390/pharmaceutics17030372Physiologically Based Pharmacokinetic Models for Infliximab, Ipilimumab, and Nivolumab Developed with GastroPlus to Predict Hepatic ConcentrationsCeleste Vallejo0Cameron Meaney1Lara Clemens2Kyunghee Yang3Viera Lukacova4Haiying Zhou5Simulations Plus, Research Triangle Park, Durham, NC 27709, USASimulations Plus, Research Triangle Park, Durham, NC 27709, USASimulations Plus, Research Triangle Park, Durham, NC 27709, USASimulations Plus, Research Triangle Park, Durham, NC 27709, USASimulations Plus, Research Triangle Park, Durham, NC 27709, USASimulations Plus, Research Triangle Park, Durham, NC 27709, USA<b>Background/Objectives:</b> Infliximab, ipilimumab, and nivolumab are three monoclonal antibodies that have been associated with hepatotoxicity. Three separate physiologically based pharmacokinetic (PBPK) models were developed in GastroPlus<sup>®</sup> to simulate plasma and liver concentrations in patient populations after administration of either infliximab, ipilimumab, or nivolumab. <b>Methods:</b> The models include distribution and clearance mechanisms specific to large molecules, FcRn binding dynamics, and target-mediated drug disposition (TNF-α for infliximab, CTLA-4 for ipilimumab, and PD-1 for nivolumab). <b>Results:</b> The PBPK model for each large molecule was able to reproduce observed plasma concentration data in patient populations, including patients with rheumatoid arthritis and patients with solid tumors. Liver concentrations were predicted to be between 10% and 23% of the plasma concentrations for each of the three drugs, aligning with previously reported results. This lends further validity to the PBPK models and their ability to accurately predict hepatic concentrations in the absence of direct tissue measurements. <b>Conclusions:</b> These results can be used to drive liver toxicity predictions using the quantitative systems toxicology model, BIOLOGXsym™, which integrates hepatic interstitial concentrations with in vitro mechanistic toxicity data to predict the extent of liver toxicity for biologics.https://www.mdpi.com/1999-4923/17/3/372physiologically based pharmacokinetic modelinfliximabipilimumabnivolumablarge moleculehepatic concentration |
| spellingShingle | Celeste Vallejo Cameron Meaney Lara Clemens Kyunghee Yang Viera Lukacova Haiying Zhou Physiologically Based Pharmacokinetic Models for Infliximab, Ipilimumab, and Nivolumab Developed with GastroPlus to Predict Hepatic Concentrations Pharmaceutics physiologically based pharmacokinetic model infliximab ipilimumab nivolumab large molecule hepatic concentration |
| title | Physiologically Based Pharmacokinetic Models for Infliximab, Ipilimumab, and Nivolumab Developed with GastroPlus to Predict Hepatic Concentrations |
| title_full | Physiologically Based Pharmacokinetic Models for Infliximab, Ipilimumab, and Nivolumab Developed with GastroPlus to Predict Hepatic Concentrations |
| title_fullStr | Physiologically Based Pharmacokinetic Models for Infliximab, Ipilimumab, and Nivolumab Developed with GastroPlus to Predict Hepatic Concentrations |
| title_full_unstemmed | Physiologically Based Pharmacokinetic Models for Infliximab, Ipilimumab, and Nivolumab Developed with GastroPlus to Predict Hepatic Concentrations |
| title_short | Physiologically Based Pharmacokinetic Models for Infliximab, Ipilimumab, and Nivolumab Developed with GastroPlus to Predict Hepatic Concentrations |
| title_sort | physiologically based pharmacokinetic models for infliximab ipilimumab and nivolumab developed with gastroplus to predict hepatic concentrations |
| topic | physiologically based pharmacokinetic model infliximab ipilimumab nivolumab large molecule hepatic concentration |
| url | https://www.mdpi.com/1999-4923/17/3/372 |
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