Extended regimen of a levonorgestrel/ethinyl estradiol transdermal delivery system: Predicted serum hormone levels using a population pharmacokinetic model.

Objective: This study employed population pharmacokinetic (popPK) models to predict levonorgestrel (LNG) and ethinyl estradiol (EE) exposure after dosing with the transdermal contraceptive TWIRLA® (LNG/EE TDS) as a 12-week extended regimen in a healthy female population.
Methods: PopPK models were developed using data from a previously published phase 1, open-label, randomized clinical trial, ATI-CL14 (NCT01243580), in 36 healthy individuals. Models used cycle 2 data from 18 individuals who received the LNG/EE TDS, delivering LNG 120 μg/day and EE 30 μg/day, followed by a 1-week TDS-free period. Noncompartmental PK analyses were performed on simulated concentration-time profiles of 12 consecutive weeks of LNG/EE TDS use.
Results: The simulated concentration-time profiles and PK parameters for the simulated extended regimen indicated that predicted LNG and EE exposures at week 12 were similar to week 3 (predicted geometric mean EE area under the concentration-time curve from time 0 to 168 h [AUC0-168] on week 3 was 0.2% lower than week 12 and LNG AUC0-168 on week 3 was 0.9% lower than week 12), suggesting both were at steady state by week 3. Therefore, no notable accumulation beyond that at week 3 is predicted for LNG and EE following a 12-week extended regimen. The results are supported by the accumulation ratios based on maximum concentration and the area under the curve being similar at weeks 3 and 12 for LNG and EE.
Conclusion: These results indicate that a 12-week extended LNG/EE regimen would provide similar systemic hormonal exposure as that seen by week 3 in a standard 28-day regimen, without further hormonal accumulation. The data support the safe use of a non-daily, low-dose hormonal contraceptive in an extended regimen but should be confirmed in a clinical PK study.
Competing Interests: Competing interests FZS: Consultant: Agile Therapeutics. DFA: Consultant: Agile Therapeutics, Bayer Healthcare, Exeltis, Mithra, Lupin, ObsEva; Grants: Bayer Healthcare, Dare Biosciences, Estetra, Myovant, ObsEva; Honoraria: Exeltis; Patent: pending; Member: DSMB; Board member: Diczfalusy foundation; Stock ownership: InnovaGyn Inc, Agile Therapeutics LRLL: Consultant: Agile Therapeutics. JP: Consultant: Agile Therapeutics. MP: Employee: Agile Therapeutics; Stock ownership: Agile Therapeutics. PK: Employee: Agile Therapeutics; Consultant: Voltron Therapeutics; Independent board director: Voltron Therapeutics; Support for business-related travel: Agile Therapeutics; Stipend: Laidlaw Venture Partners LLC Investment and Operations Committee; Stock ownership: Agile Therapeutics, Voltron Therapeutics.
(Copyright: © 2022 Stanczyk et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)