Levonorgestrel (LNG) is a progestin used in many contraceptive formulations, including subcutaneous implants. There is an unmet need for developing long-acting formulations for LNG. To develop long-acting formulations, release functions need to be investigated for LNG implant. Therefore, a release model was developed and integrated into an LNG physiologically-based pharmacokinetic (PBPK) model. Utilizing a previously developed LNG PBPK model, subcutaneous administration of 150 mg LNG was implemented into the modeling framework. To mimic LNG release, ten functions incorporating formulation-specific mechanisms were explored. Release kinetic parameters and bioavailability were optimized using Jadelle® clinical trial data (n = 321) and verified using two additional clinical trials (n = 216). The First-order release and Biexponential release models showed the best fit with observed data, the adjusted R-squared (R2) value is 0.9170. The maximum released amount is approximately 50% of the loaded dose and the release rate is 0.0009 per day. The Biexponential model also showed good agreement with the data (adjusted R2 = 0.9113). Both models could recapitulate observed plasma concentrations after integration into the PBPK simulations. First-order and Biexponential release functionality may be useful in modeling subcutaneous LNG implants. The developed model captures central tendency of the observed data as well as variability of release kinetics. Future work focuses on incorporating various clinical scenarios into model simulations, including drug-drug interactions and a range of BMIs.
Keywords: PBPK modeling; hormonal contraceptives; subcutaneous implants.