Physiologically‐Based Pharmacokinetic Model‐Informed Drug Development for Fenebrutinib: Understanding Complex Drug‐Drug Interactions
Fenebrutinib is a CYP3A substrate and time‐dependent inhibitor, as well as a BCRP and OATP1B transporter inhibitor in vitro. Physiologically‐based pharmacokinetic (PBPK) modeling strategies with the ultimate goal of understanding complex drug‐drug interactions (DDIs) and proposing doses for untested...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020-06-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.12515 |
| _version_ | 1818330526666194944 |
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| author | Yuan Chen Fang Ma Nicholas S. Jones Kenta Yoshida Po‐Chang Chiang Matthew R. Durk Matthew R. Wright Jin Yan Jin Leslie W. Chinn |
| author_facet | Yuan Chen Fang Ma Nicholas S. Jones Kenta Yoshida Po‐Chang Chiang Matthew R. Durk Matthew R. Wright Jin Yan Jin Leslie W. Chinn |
| author_sort | Yuan Chen |
| collection | DOAJ |
| description | Fenebrutinib is a CYP3A substrate and time‐dependent inhibitor, as well as a BCRP and OATP1B transporter inhibitor in vitro. Physiologically‐based pharmacokinetic (PBPK) modeling strategies with the ultimate goal of understanding complex drug‐drug interactions (DDIs) and proposing doses for untested scenarios were developed. The consistency in the results of two independent approaches, PBPK simulation and endogenous biomarker measurement, supported that the observed transporter DDI is primarily due to fenebrutinib inhibition of intestinal BCRP, rather than hepatic OATP1B. A mechanistic‐absorption model accounting for the effects of excipient complexation with fenebrutinib was used to rationalize the unexpected observation of itraconazole‐fenebrutinib DDI (maximum plasma concentration (Cmax) decreased, and area under the curve (AUC) increased). The totality of the evidence from sensitivity analysis and clinical and nonclinical data suggested that fenebrutinib is likely a sensitive CYP3A substrate. This advanced PBPK application allowed the use of model‐informed approach to facilitate the development of concomitant medication recommendations for fenebrutinib without requiring additional clinical DDI studies. |
| first_indexed | 2024-12-13T13:05:22Z |
| format | Article |
| id | doaj.art-4b03517de89446c89515dc196f2449a5 |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-12-13T13:05:22Z |
| publishDate | 2020-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-4b03517de89446c89515dc196f2449a52022-12-21T23:44:51ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062020-06-019633234110.1002/psp4.12515Physiologically‐Based Pharmacokinetic Model‐Informed Drug Development for Fenebrutinib: Understanding Complex Drug‐Drug InteractionsYuan Chen0Fang Ma1Nicholas S. Jones2Kenta Yoshida3Po‐Chang Chiang4Matthew R. Durk5Matthew R. Wright6Jin Yan Jin7Leslie W. Chinn8Department of Drug Metabolism and Pharmacokinetics Genentech, Inc. South San Francisco California USADepartment of Drug Metabolism and Pharmacokinetics Genentech, Inc. South San Francisco California USADepartment of Clinical Science Genentech, Inc. South San Francisco California USADepartment of Clinical Pharmacology Genentech, Inc. South San Francisco California USADepartment of Pharmaceutical Science Genentech, Inc. South San Francisco California USADepartment of Drug Metabolism and Pharmacokinetics Genentech, Inc. South San Francisco California USADepartment of Drug Metabolism and Pharmacokinetics Genentech, Inc. South San Francisco California USADepartment of Clinical Pharmacology Genentech, Inc. South San Francisco California USADepartment of Clinical Pharmacology Genentech, Inc. South San Francisco California USAFenebrutinib is a CYP3A substrate and time‐dependent inhibitor, as well as a BCRP and OATP1B transporter inhibitor in vitro. Physiologically‐based pharmacokinetic (PBPK) modeling strategies with the ultimate goal of understanding complex drug‐drug interactions (DDIs) and proposing doses for untested scenarios were developed. The consistency in the results of two independent approaches, PBPK simulation and endogenous biomarker measurement, supported that the observed transporter DDI is primarily due to fenebrutinib inhibition of intestinal BCRP, rather than hepatic OATP1B. A mechanistic‐absorption model accounting for the effects of excipient complexation with fenebrutinib was used to rationalize the unexpected observation of itraconazole‐fenebrutinib DDI (maximum plasma concentration (Cmax) decreased, and area under the curve (AUC) increased). The totality of the evidence from sensitivity analysis and clinical and nonclinical data suggested that fenebrutinib is likely a sensitive CYP3A substrate. This advanced PBPK application allowed the use of model‐informed approach to facilitate the development of concomitant medication recommendations for fenebrutinib without requiring additional clinical DDI studies.https://doi.org/10.1002/psp4.12515 |
| spellingShingle | Yuan Chen Fang Ma Nicholas S. Jones Kenta Yoshida Po‐Chang Chiang Matthew R. Durk Matthew R. Wright Jin Yan Jin Leslie W. Chinn Physiologically‐Based Pharmacokinetic Model‐Informed Drug Development for Fenebrutinib: Understanding Complex Drug‐Drug Interactions CPT: Pharmacometrics & Systems Pharmacology |
| title | Physiologically‐Based Pharmacokinetic Model‐Informed Drug Development for Fenebrutinib: Understanding Complex Drug‐Drug Interactions |
| title_full | Physiologically‐Based Pharmacokinetic Model‐Informed Drug Development for Fenebrutinib: Understanding Complex Drug‐Drug Interactions |
| title_fullStr | Physiologically‐Based Pharmacokinetic Model‐Informed Drug Development for Fenebrutinib: Understanding Complex Drug‐Drug Interactions |
| title_full_unstemmed | Physiologically‐Based Pharmacokinetic Model‐Informed Drug Development for Fenebrutinib: Understanding Complex Drug‐Drug Interactions |
| title_short | Physiologically‐Based Pharmacokinetic Model‐Informed Drug Development for Fenebrutinib: Understanding Complex Drug‐Drug Interactions |
| title_sort | physiologically based pharmacokinetic model informed drug development for fenebrutinib understanding complex drug drug interactions |
| url | https://doi.org/10.1002/psp4.12515 |
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