INTRODUCTION: To characterize performance of the levonorgestrel releasing intrauterine system (LNG-IUS) 52 mg (Mirena) for 8 years of use (currently approved for 7 years) and facilitate comparisons with LNG-IUS 19.5 mg and LNG-IUS 13.5 mg, we estimated in vivo LNG release rates and LNG plasma/serum concentrations using a population pharmacokinetic (popPK) approach with data from the Mirena Extension Trial (MET) and earlier clinical trials. METHODS: Previously, we developed a popPK model based on measured plasma/serum LNG concentrations and residual LNG content from removed 52 mg, 19.5 mg, and 13.5 mg LNG-IUS devices in clinical studies for up to 5 years of use, estimating in vivo LNG release and describing LNG exposure. To estimate release and exposure for years 6–8 of use, we applied the model to data for 6, 7, and finally 8 years from the MET. RESULTS: As expected, LNG release rates for LNG-IUS 52 mg were higher than for 19.5 mg and 13.5 mg devices. After 8 years, LNG-IUS 52 mg release rate (7.04 µg/day) was similar to LNG-IUS 19.5 mg after 5 years (7.6 µg/day) and higher than LNG-IUS 13.5 mg after 3 years (5.5 µg/day). Model-based estimated and measured LNG concentrations showed good agreement, with average plasma LNG concentrations after 8 years LNG-IUS 52 mg (100ng/L [CV%: 39.9%]) similar to after 5 years LNG-IUS 19.5 mg (84.8ng/L [39.9%]) and higher than after 3 years LNG-IUS 13.5 mg (58.1ng/L [40.8%]) use. CONCLUSION: LNG release rates from LNG-IUS 52 mg at 8 years are similar to 19.5 mg at 5 years and higher than 13.5 mg at 3 years. The 8-year popPK model provides in vivo LNG release rate and concentration estimates, facilitating more direct comparisons between the three LNG-IUSs. [ABSTRACT FROM AUTHOR]