Extended Use of Levonorgestrel-Releasing Intrauterine System (LNG-IUS) 52 mg: A Population Pharmacokinetic Approach to Estimate In Vivo Levonorgestrel Release Rates and Systemic Exposure Including Comparison With Two Other LNG-IUSs Comment

To characterize performance of levonorgestrel-releasing intrauterine system (LNG-IUS) 52mg (Mirena) over 8 years of use and facilitate comparisons with LNG-IUS 19.5mg and LNG-IUS 13.5mg.We estimated in vivo levonorgestrel (LNG) release rates and LNG plasma/serum concentrations for LNG-IUS 52mg up to 8 years of use with a population pharmacokinetic (popPK) approach using data from the Mirena Extension Trial (MET) and earlier clinical trials. We compared these with previously published release rates and exposure data for LNG-IUS 19.5mg and 13.5mg. Our 8-year popPK and release models were developed based on measured plasma/serum LNG and sex hormone-binding globulin concentrations and residual LNG content from removed LNG-IUS 52mg devices.Model-based estimated LNG release rates for LNG-IUS 52mg decreased from ∼21 µg/d after insertion to ∼7.0 µg/d after 8 years, similar to LNG-IUS 19.5mg after 5 years (7.6 µg/d) and higher than LNG-IUS 13.5mg after 3 years (5.5 µg/d). Model-based estimated and measured plasma/serum LNG concentrations showed satisfactory agreement. Average model-based estimated LNG concentrations after 8 years of LNG-IUS 52mg use (100 ng/L [coefficient of variance 39.9%]) were similar to LNG-IUS 19.5mg after 5 years (84.8 ng/L [39.9%]) and higher than LNG-IUS 13.5mg after 3 years (58.1 ng/L [40.8%]).The 8-year release and popPK models provide reliable in vivo LNG release rates and concentration estimates, respectively, facilitating direct comparisons between the 3 studied LNG-IUSs. LNG release rates from LNG-IUS 52mg at 8 years are similar to LNG-IUS 19.5mg at 5 years and higher than LNG-IUS 13.5mg at 3 years.Levonorgestrel release from intrauterine system reservoirs declines with duration of use in a predictable way, and in relation to the initial load. As release rates and plasma concentrations of levonorgestrel may influence endometrial and systemic side effects, these data may assist clinical decision-making.