Physiologically‐based pharmacokinetic modeling of prominent oral contraceptive agents and applications in drug–drug interactions
Abstract Considerable interest remains across the pharmaceutical industry and regulatory landscape in capabilities to model oral contraceptives (OCs), whether combined (COCs) with ethinyl estradiol (EE) or progestin‐only pill. Acceptance of COC drug–drug interaction (DDI) assessment using physiologi...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Wiley
2024-04-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.13101 |
| _version_ | 1797209919679627264 |
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| author | Gareth J. Lewis Deepak Ahire Kunal S. Taskar |
| author_facet | Gareth J. Lewis Deepak Ahire Kunal S. Taskar |
| author_sort | Gareth J. Lewis |
| collection | DOAJ |
| description | Abstract Considerable interest remains across the pharmaceutical industry and regulatory landscape in capabilities to model oral contraceptives (OCs), whether combined (COCs) with ethinyl estradiol (EE) or progestin‐only pill. Acceptance of COC drug–drug interaction (DDI) assessment using physiologically‐based pharmacokinetic (PBPK) is often limited to the estrogen component (EE), requiring further verification, with extrapolation from EE to progestins discouraged. There is a paucity of published progestin component PBPK models to support the regulatory DDI guidance for industry to evaluate a new chemical entity's (NCE's) DDI potential with COCs. Guidance recommends a clinical interaction study to be considered if an investigational drug is a weak or moderate inducer, or a moderate/strong inhibitor, of CYP3A4. Therefore, availability of validated OC PBPK models within one software platform, will be useful in predicting the DDI potential with NCEs earlier in the clinical development. Thus, this work was focused on developing and validating PBPK models for progestins, DNG, DRSP, LNG, and NET, within Simcyp, and assessing the DDI potential with known CYP3A4 inhibitors (e.g., ketoconazole) and inducers (e.g., rifampicin) with published clinical data. In addition, this work demonstrated confidence in the Simcyp EE model for regulatory and clinical applications by extensive verification in 70+ clinical PK and CYP3A4 interaction studies. The results provide greater capability to prospectively model clinical CYP3A4 DDI with COCs using Simcyp PBPK to interrogate the regulatory decision‐tree to contextualize the potential interaction by known perpetrators and NCEs, enabling model‐informed decision making, clinical study designs, and delivering potential alternative COC options for women of childbearing potential. |
| first_indexed | 2024-04-24T10:02:21Z |
| format | Article |
| id | doaj.art-beb21c25bba444ed8d163c8586de4efc |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-04-24T10:02:21Z |
| publishDate | 2024-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-beb21c25bba444ed8d163c8586de4efc2024-04-13T05:41:26ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062024-04-0113456357510.1002/psp4.13101Physiologically‐based pharmacokinetic modeling of prominent oral contraceptive agents and applications in drug–drug interactionsGareth J. Lewis0Deepak Ahire1Kunal S. Taskar2Drug Metabolism and Pharmacokinetics, In Vitro In Vivo Translation, Research, GlaxoSmithKline Stevenage UKDepartment of Pharmaceutical Sciences Washington State University Spokane Washington USADrug Metabolism and Pharmacokinetics, In Vitro In Vivo Translation, Research, GlaxoSmithKline Stevenage UKAbstract Considerable interest remains across the pharmaceutical industry and regulatory landscape in capabilities to model oral contraceptives (OCs), whether combined (COCs) with ethinyl estradiol (EE) or progestin‐only pill. Acceptance of COC drug–drug interaction (DDI) assessment using physiologically‐based pharmacokinetic (PBPK) is often limited to the estrogen component (EE), requiring further verification, with extrapolation from EE to progestins discouraged. There is a paucity of published progestin component PBPK models to support the regulatory DDI guidance for industry to evaluate a new chemical entity's (NCE's) DDI potential with COCs. Guidance recommends a clinical interaction study to be considered if an investigational drug is a weak or moderate inducer, or a moderate/strong inhibitor, of CYP3A4. Therefore, availability of validated OC PBPK models within one software platform, will be useful in predicting the DDI potential with NCEs earlier in the clinical development. Thus, this work was focused on developing and validating PBPK models for progestins, DNG, DRSP, LNG, and NET, within Simcyp, and assessing the DDI potential with known CYP3A4 inhibitors (e.g., ketoconazole) and inducers (e.g., rifampicin) with published clinical data. In addition, this work demonstrated confidence in the Simcyp EE model for regulatory and clinical applications by extensive verification in 70+ clinical PK and CYP3A4 interaction studies. The results provide greater capability to prospectively model clinical CYP3A4 DDI with COCs using Simcyp PBPK to interrogate the regulatory decision‐tree to contextualize the potential interaction by known perpetrators and NCEs, enabling model‐informed decision making, clinical study designs, and delivering potential alternative COC options for women of childbearing potential.https://doi.org/10.1002/psp4.13101 |
| spellingShingle | Gareth J. Lewis Deepak Ahire Kunal S. Taskar Physiologically‐based pharmacokinetic modeling of prominent oral contraceptive agents and applications in drug–drug interactions CPT: Pharmacometrics & Systems Pharmacology |
| title | Physiologically‐based pharmacokinetic modeling of prominent oral contraceptive agents and applications in drug–drug interactions |
| title_full | Physiologically‐based pharmacokinetic modeling of prominent oral contraceptive agents and applications in drug–drug interactions |
| title_fullStr | Physiologically‐based pharmacokinetic modeling of prominent oral contraceptive agents and applications in drug–drug interactions |
| title_full_unstemmed | Physiologically‐based pharmacokinetic modeling of prominent oral contraceptive agents and applications in drug–drug interactions |
| title_short | Physiologically‐based pharmacokinetic modeling of prominent oral contraceptive agents and applications in drug–drug interactions |
| title_sort | physiologically based pharmacokinetic modeling of prominent oral contraceptive agents and applications in drug drug interactions |
| url | https://doi.org/10.1002/psp4.13101 |
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