TY - JOUR
T1 - Determining the Exposure Threshold for Levonorgestrel Efficacy Using an Integrated Model Based Meta-Analysis Approach
AU - Lingineni, Karthik
AU - Chaturvedula, Ayyappa
AU - Cicali, Brian
AU - Cristofoletti, Rodrigo
AU - Wendl, Thomas
AU - Hoechel, Joachim
AU - Brown, Joshua D.
AU - Vozmediano, Valvanera
AU - Schmidt, Stephan
N1 - Funding Information:
The project was financially supported by the Bill & Melinda Gates Foundation (Grant number OPP1185454).
Funding Information:
The project was financially supported by the Bill & Melinda Gates Foundation (Grant number OPP1185454). The authors would like to acknowledge Excelra Knowledge Solutions Pvt. Ltd., Hyderabad, India, for the contributions in conducting extensive literature search and compiling the references across different databases. The authors would also like to acknowledge Martin Ulbricht and Katharina Wieser for their contributions in the additional literature search.
Publisher Copyright:
© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics
PY - 2022/2
Y1 - 2022/2
N2 - Combined oral contraceptive pills are the most commonly used hormonal contraceptives for the prevention of unintended pregnancies in United States. They consist of a progestin (e.g., levonorgestrel (LNG)) and an estrogen component, typically ethinyl estradiol (EE). In addition to adherence issues, drug-drug interactions (DDIs) and obesity (women with body mass index (BMI) ≥ 30 kg/m2) are prime suspects for decreased LNG efficacy. Therefore, we developed an integrated physiologically-based pharmacokinetic modeling and model-based meta-analysis approach to determine LNG’s efficacy threshold concentrations and to evaluate the impact of DDIs and obesity on the efficacy of LNG-containing hormonal contraceptives (HCs). Based on this approach, co-administration of strong CYP3A4 inducers and LNG-containing HCs (LNG150: LNG 150 µg + EE 30 µg and LNG100: LNG 100 µg + EE 20 µg) resulted in a predicted clinically relevant decrease of LNG plasma exposure (women with BMI < 25 kg/m2: 50–65%; obese women: 70–75%). Following administration of LNG150 or LNG100 in the presence of a CYP3A4 inducer, there was an increase in mean Pearl Index of 1.2–1.30 and 1.80–2.10, respectively, in women with BMI < 25 kg/m2 (incidence rate ratios (IRRs): 1.7–2.2), whereas it ranged from 1.6–1.80 and 2.40–2.85 in obese women (IRR: 2.2–3.0), respectively. Our results suggest that the use of backup or alternate methods of contraception is not necessarily required for oral LNG + EE formulations except within circumstances of both obesity and strong CYP3A4 inducer concomitance following administration of LNG100.
AB - Combined oral contraceptive pills are the most commonly used hormonal contraceptives for the prevention of unintended pregnancies in United States. They consist of a progestin (e.g., levonorgestrel (LNG)) and an estrogen component, typically ethinyl estradiol (EE). In addition to adherence issues, drug-drug interactions (DDIs) and obesity (women with body mass index (BMI) ≥ 30 kg/m2) are prime suspects for decreased LNG efficacy. Therefore, we developed an integrated physiologically-based pharmacokinetic modeling and model-based meta-analysis approach to determine LNG’s efficacy threshold concentrations and to evaluate the impact of DDIs and obesity on the efficacy of LNG-containing hormonal contraceptives (HCs). Based on this approach, co-administration of strong CYP3A4 inducers and LNG-containing HCs (LNG150: LNG 150 µg + EE 30 µg and LNG100: LNG 100 µg + EE 20 µg) resulted in a predicted clinically relevant decrease of LNG plasma exposure (women with BMI < 25 kg/m2: 50–65%; obese women: 70–75%). Following administration of LNG150 or LNG100 in the presence of a CYP3A4 inducer, there was an increase in mean Pearl Index of 1.2–1.30 and 1.80–2.10, respectively, in women with BMI < 25 kg/m2 (incidence rate ratios (IRRs): 1.7–2.2), whereas it ranged from 1.6–1.80 and 2.40–2.85 in obese women (IRR: 2.2–3.0), respectively. Our results suggest that the use of backup or alternate methods of contraception is not necessarily required for oral LNG + EE formulations except within circumstances of both obesity and strong CYP3A4 inducer concomitance following administration of LNG100.
UR - http://www.scopus.com/inward/record.url?scp=85118560672&partnerID=8YFLogxK
U2 - 10.1002/cpt.2457
DO - 10.1002/cpt.2457
M3 - Article
C2 - 34674227
AN - SCOPUS:85118560672
SN - 0009-9236
VL - 111
SP - 509
EP - 518
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
IS - 2
ER -