Quantitative Assessment of Levonorgestrel Binding Partner Interplay and Drug-Drug Interactions Using Physiologically Based Pharmacokinetic Modeling.

CPT: Pharmacometrics & Systems Pharmacology
Brian CicaliStephan Schmidt

Abstract

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/m2 ) with and without co-administration of itraconazole (competitive CYP3A4 inhibitor) and...Continue Reading

References

May 1, 1977·Journal of Pharmaceutical Sciences·A R Hurwitz, S T Liu
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Apr 29, 2005·Journal of Pharmaceutical Sciences·Trudy RodgersMalcolm Rowland
Aug 4, 2009·Molecular and Cellular Endocrinology·Thomas E Willnow, Anders Nykjaer
May 18, 2010·Contraception·Carolyn L WesthoffFrank Z Stanczyk
Apr 27, 2012·Infectious Diseases in Obstetrics and Gynecology·Monica L CartenSusan Cu-Uvin
Sep 19, 2011·Clinical Medicine Insights. Reproductive Health·Rachel A Bonnema, Abby L Spencer
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Aug 21, 2016·Contraception·William J Jusko
Oct 8, 2017·Clinical and Translational Science·Nan ZhangLi Li
Sep 28, 2018·CPT: Pharmacometrics & Systems Pharmacology·Lawrence J LeskoStephan Schmidt

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Methods Mentioned

BETA
contraception

Software Mentioned

PK
Sim

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