LB-037 - UTILIZING MODEL BASED META-ANALYSIS TO CHARACTERIZE BREAKTHROUGH BLEEDING AND SPOTTING IN WOMEN USING HORMONAL CONTRACEPTIVES

H. Chen¹, D. Chun¹, K. Lingineni², S. Guzy², B. Cicali¹, R. Cristofoletti¹, V. Vozmediano¹, S. Schmidt²; ¹Univ of Florida Coll of Pharmacy, Orlando, FL, United States, ²University of Florida, , .

Background: Combined oral contraceptives (COCs) are critical for preventing unintended pregnancy in women of childbearing age. Adverse effects, notably breakthrough bleeding/ spotting (BTB/BTS), can lead to COC discontinuation and increase unintended pregnancy risk. The quantitative relationship between progestin-induced BTB/BTS and EE's protective effects remains unestablished due to formulation and dosage variations. This study aimed to establish a COC-BTB/BTS dose-response relationship through a model-based meta-analysis (MBMA).

Methods: A systematic literature search was conducted via PubMed, Cochrane and EMBASE databases for common COCs and their respective reports of BTB/BTS. BTB/BTS definitions, patients and trial information were screened for data consistency. The final database for the MBMA analysis included 37 digitized studies. The time course of BTB/BTS was quantified with an exponential decline model to account for changes during COC treatment. A global sensitivity analysis was performed to assess the impact of covariates on BTB/BTS incidents over time.

Results: The data showed a substantial 5 to 15-fold increase in BTB and a 7 to 23-fold increase in BTB/BTS from baseline upon COC initiation. MBMA indicated a slow mono-exponential BTB/BTS decline in progestin-only pill users. In COC users, EE initially caused a rapid decrease in BTB/BTS, gradually returning to baseline after about 6 to 12 months for BTB or BTB/BTS. This final MBMA model effectively captured progestin-induced BTB/BTS and EE's protective effects. The global sensitivity analysis emphasized the critical roles of progestin type and EE dosage in shaping the decline of BTB/BTS incidents over time.

Conclusion: We quantitatively characterize the relationship of different progestins, EE and BTB/BTS over time using a MBMA. The results confirmed that the increase in BTB differs from baseline by progestin and dose, while EE provides protection. This newly established dose-response relationship for COCs and BTB/BTS will guide future work, incorporating physiologically-based pharmacokinetic modeling to establish an exposure-response model and explore clinical scenarios like CYP3A4 drug-drug interactions and obesity. Ultimately, our research aims to inform dose selection and justify COC use to reduce the occurrence of BTB/BTS in various clinical scenarios.