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Quantitative Assessment of Levonorgestrel Binding Partner Interplay and Drug‐Drug Interactions Using Physiologically Based Pharmacokinetic Modeling
Levonorgestrel (LNG) is the active moiety in many hormonal contraceptive formulations. It is typically coformulated with ethinyl estradiol (EE) to decrease intermenstrual bleeding. Due to its widespread use and CYP3A4‐mediated metabolism, there is concern regarding drug‐drug interactions (DDIs), par...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825189/ https://www.ncbi.nlm.nih.gov/pubmed/33217171 http://dx.doi.org/10.1002/psp4.12572 |
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author | Cicali, Brian Lingineni, Karthik Cristofoletti, Rodrigo Wendl, Thomas Hoechel, Joachim Wiesinger, Herbert Chaturvedula, Ayyappa Vozmediano, Valvanera Schmidt, Stephan |
author_facet | Cicali, Brian Lingineni, Karthik Cristofoletti, Rodrigo Wendl, Thomas Hoechel, Joachim Wiesinger, Herbert Chaturvedula, Ayyappa Vozmediano, Valvanera Schmidt, Stephan |
author_sort | Cicali, Brian |
collection | PubMed |
description | Levonorgestrel (LNG) is the active moiety in many hormonal contraceptive formulations. It is typically coformulated with ethinyl estradiol (EE) to decrease intermenstrual bleeding. Due to its widespread use and CYP3A4‐mediated metabolism, there is concern regarding drug‐drug interactions (DDIs), particularly a suboptimal LNG exposure when co‐administered with CYP3A4 inducers, potentially leading to unintended pregnancies. The goal of this analysis was to determine the impact of DDIs on the systemic exposure of LNG. To this end, we developed and verified a physiologically‐based pharmacokinetic (PBPK) model for LNG in PK‐Sim (version 8.0) accounting for the impact of EE and body mass index (BMI) on LNG’s binding to sex‐hormone binding globulin. Model parameters were optimized following intravenous and oral administration of 0.09 mg LNG. The combined LNG‐EE PBPK model was verified regarding CYP3A4‐mediated interaction by comparing to published clinical DDI study data with carbamazepine, rifampicin, and efavirenz (CYP3A4 inducers). Once verified, the model was applied to predict systemic LNG exposure in normal BMI and obese women (BMI ≥ 30 kg/m(2)) with and without co‐administration of itraconazole (competitive CYP3A4 inhibitor) and clarithromycin (mechanism‐based CYP3A4 inhibitor). Total and free LNG exposures, when co‐administered with EE, decreased 2‐fold in the presence of rifampin, whereas they increased 1.5‐fold in the presence of itraconazole. Although changes in total and unbound exposure were decreased in obese women compared with normal BMI women, the relative impact of DDIs on LNG exposure was similar between both groups. |
format | Online Article Text |
id | pubmed-7825189 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-78251892021-02-01 Quantitative Assessment of Levonorgestrel Binding Partner Interplay and Drug‐Drug Interactions Using Physiologically Based Pharmacokinetic Modeling Cicali, Brian Lingineni, Karthik Cristofoletti, Rodrigo Wendl, Thomas Hoechel, Joachim Wiesinger, Herbert Chaturvedula, Ayyappa Vozmediano, Valvanera Schmidt, Stephan CPT Pharmacometrics Syst Pharmacol Research Levonorgestrel (LNG) is the active moiety in many hormonal contraceptive formulations. It is typically coformulated with ethinyl estradiol (EE) to decrease intermenstrual bleeding. Due to its widespread use and CYP3A4‐mediated metabolism, there is concern regarding drug‐drug interactions (DDIs), particularly a suboptimal LNG exposure when co‐administered with CYP3A4 inducers, potentially leading to unintended pregnancies. The goal of this analysis was to determine the impact of DDIs on the systemic exposure of LNG. To this end, we developed and verified a physiologically‐based pharmacokinetic (PBPK) model for LNG in PK‐Sim (version 8.0) accounting for the impact of EE and body mass index (BMI) on LNG’s binding to sex‐hormone binding globulin. Model parameters were optimized following intravenous and oral administration of 0.09 mg LNG. The combined LNG‐EE PBPK model was verified regarding CYP3A4‐mediated interaction by comparing to published clinical DDI study data with carbamazepine, rifampicin, and efavirenz (CYP3A4 inducers). Once verified, the model was applied to predict systemic LNG exposure in normal BMI and obese women (BMI ≥ 30 kg/m(2)) with and without co‐administration of itraconazole (competitive CYP3A4 inhibitor) and clarithromycin (mechanism‐based CYP3A4 inhibitor). Total and free LNG exposures, when co‐administered with EE, decreased 2‐fold in the presence of rifampin, whereas they increased 1.5‐fold in the presence of itraconazole. Although changes in total and unbound exposure were decreased in obese women compared with normal BMI women, the relative impact of DDIs on LNG exposure was similar between both groups. John Wiley and Sons Inc. 2020-12-13 2021-01 /pmc/articles/PMC7825189/ /pubmed/33217171 http://dx.doi.org/10.1002/psp4.12572 Text en © 2020 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Cicali, Brian Lingineni, Karthik Cristofoletti, Rodrigo Wendl, Thomas Hoechel, Joachim Wiesinger, Herbert Chaturvedula, Ayyappa Vozmediano, Valvanera Schmidt, Stephan Quantitative Assessment of Levonorgestrel Binding Partner Interplay and Drug‐Drug Interactions Using Physiologically Based Pharmacokinetic Modeling |
title | Quantitative Assessment of Levonorgestrel Binding Partner Interplay and Drug‐Drug Interactions Using Physiologically Based Pharmacokinetic Modeling |
title_full | Quantitative Assessment of Levonorgestrel Binding Partner Interplay and Drug‐Drug Interactions Using Physiologically Based Pharmacokinetic Modeling |
title_fullStr | Quantitative Assessment of Levonorgestrel Binding Partner Interplay and Drug‐Drug Interactions Using Physiologically Based Pharmacokinetic Modeling |
title_full_unstemmed | Quantitative Assessment of Levonorgestrel Binding Partner Interplay and Drug‐Drug Interactions Using Physiologically Based Pharmacokinetic Modeling |
title_short | Quantitative Assessment of Levonorgestrel Binding Partner Interplay and Drug‐Drug Interactions Using Physiologically Based Pharmacokinetic Modeling |
title_sort | quantitative assessment of levonorgestrel binding partner interplay and drug‐drug interactions using physiologically based pharmacokinetic modeling |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825189/ https://www.ncbi.nlm.nih.gov/pubmed/33217171 http://dx.doi.org/10.1002/psp4.12572 |
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