Abstract
An intrauterine system (IUS) can be implanted in the uterus and deliver drug directly at the site of pharmacological action. Mirena was the first FDA-approved levonorgestrel (LNG) releasing IUS without an approved generic form. Its 5-year application duration presents challenges for bioequivalence (BE) assessment using the conventional in vivo studies with pharmacokinetic and/or comparative clinical endpoints. Conventionally, along with other conditions, BE could be established if the 90% confidence interval (CI) of the ratio of geometric means of residual LNG at the end of 5 years is within the BE limits of 80.00% and 125.00%. Modeling and simulation were conducted to identify a shortened BE study duration and its corresponding BE acceptance limit that can be used as a surrogate for the conventional limit for a 5-year study. Simulation results suggest that having the 90% CI of the residual LNG 12 months post insertion within 95.00–105.26% would ensure that residual LNG amount at 5 years to be within 80.00–125.00%. This modeling and simulation practice leads to the current BE recommendation: if a test IUS is made of the same material in the same concentration and has the same physical dimensions as the Mirena, its BE could be established by showing (1) comparative physicochemical and mechanical properties; (2) comparative in vitro drug release behavior for 5 years; and (3) performance in a comparative short-term in vivo study and BE based on 90% confidence interval of test and reference ratio of residual LNG to be within 95.00–105.26% at month 12.
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Authors thank Joanne Berger (FDA Library) for manuscript editing assistance.
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Conception design or planning of the study: Satish Sharan, Sungwoo Choi, Fairouz Makhlouf, Stella C Grosser, Xinyuan Zhang, Stephanie Choi, and Liang Zhao.
Acquisition of the data: Satish Sharan and Sungwoo Choi.
Analysis of the data: Satish Sharan and Sungwoo Choi.
Interpretation of the results: Satish Sharan, Sungwoo Choi, Xinyuan Zhang, Fairouz Makhlouf, Stella C Grosser, and Liang Zhao.
Critically reviewing or revising the manuscript for important intellectual content: Satish Sharan, Sungwoo Choi, Yuan Zou, Yan Wang, Myong-Jin Kim, Lanyan Fang, Stephanie Choi, Fairouz Makhlouf, Stella C Grosser, Xinyuan Zhang, and Liang Zhao.
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Sharan, S., Choi, S., Zou, Y. et al. Application of Modeling and Simulation to Identify a Shortened Study Duration and Novel Bioequivalence Metric for a Long-Acting Intrauterine System. AAPS J 24, 63 (2022). https://doi.org/10.1208/s12248-022-00715-z
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DOI: https://doi.org/10.1208/s12248-022-00715-z