A Physiologically Based Pharmacokinetic Model to Predict Determinants of Variability in Epirubicin Exposure and Tissue Distribution
Background: Epirubicin is an anthracycline antineoplastic drug that is primarily used in combination therapies for the treatment of breast, gastric, lung and ovarian cancers and lymphomas. Epirubicin is administered intravenously (IV) over 3 to 5 min once every 21 days with dosing based on body surf...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-04-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/4/1222 |
| _version_ | 1797603910013157376 |
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| author | Radwan Ansaar Robyn Meech Andrew Rowland |
| author_facet | Radwan Ansaar Robyn Meech Andrew Rowland |
| author_sort | Radwan Ansaar |
| collection | DOAJ |
| description | Background: Epirubicin is an anthracycline antineoplastic drug that is primarily used in combination therapies for the treatment of breast, gastric, lung and ovarian cancers and lymphomas. Epirubicin is administered intravenously (IV) over 3 to 5 min once every 21 days with dosing based on body surface area (BSA; mg/m<sup>2</sup>). Despite accounting for BSA, marked inter-subject variability in circulating epirubicin plasma concentration has been reported. Methods: In vitro experiments were conducted to determine the kinetics of epirubicin glucuronidation by human liver microsomes in the presence and absence of validated UGT2B7 inhibitors. A full physiologically based pharmacokinetic model was built and validated using Simcyp<sup>®</sup> (version 19.1, Certara, Princeton, NJ, USA). The model was used to simulate epirubicin exposure in 2000 Sim-Cancer subjects over 158 h following a single intravenous dose of epirubicin. A multivariable linear regression model was built using simulated demographic and enzyme abundance data to determine the key drivers of variability in systemic epirubicin exposure. Results: Multivariable linear regression modelling demonstrated that variability in simulated systemic epirubicin exposure following intravenous injection was primarily driven by differences in hepatic and renal UGT2B7 expression, plasma albumin concentration, age, BSA, GFR, haematocrit and sex. By accounting for these factors, it was possible to explain 87% of the variability in epirubicin in a simulated cohort of 2000 oncology patients. Conclusions: The present study describes the development and evaluation of a full-body PBPK model to assess systemic and individual organ exposure to epirubicin. Variability in epirubicin exposure was primarily driven by hepatic and renal UGT2B7 expression, plasma albumin concentration, age, BSA, GFR, haematocrit and sex. |
| first_indexed | 2024-03-11T04:38:45Z |
| format | Article |
| id | doaj.art-e55762590cae4657a4aff728b5b31ac9 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T04:38:45Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-e55762590cae4657a4aff728b5b31ac92023-11-17T20:54:27ZengMDPI AGPharmaceutics1999-49232023-04-01154122210.3390/pharmaceutics15041222A Physiologically Based Pharmacokinetic Model to Predict Determinants of Variability in Epirubicin Exposure and Tissue DistributionRadwan Ansaar0Robyn Meech1Andrew Rowland2College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, AustraliaCollege of Medicine and Public Health, Flinders University, Adelaide, SA 5042, AustraliaCollege of Medicine and Public Health, Flinders University, Adelaide, SA 5042, AustraliaBackground: Epirubicin is an anthracycline antineoplastic drug that is primarily used in combination therapies for the treatment of breast, gastric, lung and ovarian cancers and lymphomas. Epirubicin is administered intravenously (IV) over 3 to 5 min once every 21 days with dosing based on body surface area (BSA; mg/m<sup>2</sup>). Despite accounting for BSA, marked inter-subject variability in circulating epirubicin plasma concentration has been reported. Methods: In vitro experiments were conducted to determine the kinetics of epirubicin glucuronidation by human liver microsomes in the presence and absence of validated UGT2B7 inhibitors. A full physiologically based pharmacokinetic model was built and validated using Simcyp<sup>®</sup> (version 19.1, Certara, Princeton, NJ, USA). The model was used to simulate epirubicin exposure in 2000 Sim-Cancer subjects over 158 h following a single intravenous dose of epirubicin. A multivariable linear regression model was built using simulated demographic and enzyme abundance data to determine the key drivers of variability in systemic epirubicin exposure. Results: Multivariable linear regression modelling demonstrated that variability in simulated systemic epirubicin exposure following intravenous injection was primarily driven by differences in hepatic and renal UGT2B7 expression, plasma albumin concentration, age, BSA, GFR, haematocrit and sex. By accounting for these factors, it was possible to explain 87% of the variability in epirubicin in a simulated cohort of 2000 oncology patients. Conclusions: The present study describes the development and evaluation of a full-body PBPK model to assess systemic and individual organ exposure to epirubicin. Variability in epirubicin exposure was primarily driven by hepatic and renal UGT2B7 expression, plasma albumin concentration, age, BSA, GFR, haematocrit and sex.https://www.mdpi.com/1999-4923/15/4/1222PBPKepirubicinpharmacokineticsdrug exposure |
| spellingShingle | Radwan Ansaar Robyn Meech Andrew Rowland A Physiologically Based Pharmacokinetic Model to Predict Determinants of Variability in Epirubicin Exposure and Tissue Distribution Pharmaceutics PBPK epirubicin pharmacokinetics drug exposure |
| title | A Physiologically Based Pharmacokinetic Model to Predict Determinants of Variability in Epirubicin Exposure and Tissue Distribution |
| title_full | A Physiologically Based Pharmacokinetic Model to Predict Determinants of Variability in Epirubicin Exposure and Tissue Distribution |
| title_fullStr | A Physiologically Based Pharmacokinetic Model to Predict Determinants of Variability in Epirubicin Exposure and Tissue Distribution |
| title_full_unstemmed | A Physiologically Based Pharmacokinetic Model to Predict Determinants of Variability in Epirubicin Exposure and Tissue Distribution |
| title_short | A Physiologically Based Pharmacokinetic Model to Predict Determinants of Variability in Epirubicin Exposure and Tissue Distribution |
| title_sort | physiologically based pharmacokinetic model to predict determinants of variability in epirubicin exposure and tissue distribution |
| topic | PBPK epirubicin pharmacokinetics drug exposure |
| url | https://www.mdpi.com/1999-4923/15/4/1222 |
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