Phase I/II pharmacokinetic and pharmacodynamic evaluation of two levonorgestrel-only contraceptive patches in a multicenter randomized trial

Carolyn L Westhoff; Beatrice A Chen; Jeffrey T Jensen; Kurt Barnhart; Michael Thomas; Stephanie Teal; Diana Blithe

doi:10.1016/j.contraception.2018.04.007

Phase I/II pharmacokinetic and pharmacodynamic evaluation of two levonorgestrel-only contraceptive patches in a multicenter randomized trial

Contraception. 2018 Apr 18:S0010-7824(18)30143-4. doi: 10.1016/j.contraception.2018.04.007. Online ahead of print.

Authors

Carolyn L Westhoff¹, Beatrice A Chen², Jeffrey T Jensen³, Kurt Barnhart⁴, Michael Thomas⁵, Stephanie Teal⁶, Diana Blithe⁷

Affiliations

¹ Columbia University. Electronic address: clw3@columbia.edu.
² University of Pittsburgh/Magee-Womens Research Institute.
³ Oregon Health and Science University.
⁴ University of Pennsylvania.
⁵ University of Cincinnati.
⁶ University of Colorado.
⁷ National Institute of Child Health and Human Development.

PMID: 29679590
DOI: 10.1016/j.contraception.2018.04.007

Abstract

Objectives: To evaluate the pharmacokinetic and pharmacodynamic effects of two novel levonorgestrel (LNG)-only contraceptive patches.

Study design: This multi-center Phase I/II trial randomized participants to use a 7-day transdermal patch designed to deliver a 40 mcg or 75 mcg daily LNG dose for 11 consecutive weeks; randomization was stratified by body mass index (BMI) <32 or 32-40 kg/m². Evaluations occurred twice weekly for 5 weeks, then once weekly with supplemental visits for participants reporting a urinary LH surge. We evaluated pharmacokinetics via the weekly trough serum LNG concentrations (≥180 pg/mL considered therapeutic). The primary pharmacodynamic outcomes were cervical mucus and ovulation, evaluated using modified Insler cervical mucus scores and serum markers of ovulation.

Results: Randomization yielded similar groups. Of 121 enrolled women, 117 contributed analyzable data. Overall, mean LNG concentrations achieved with use of the 75 mcg patch [value] were roughly double those seen with the 40 mcg dose. Concentrations achieved in higher-BMI women (BMI=32-40 kg/m²) were 50% lower compared to lower-BMI women for both patches. During the study, 94/117 (80%) participants had at least one LNG concentration <180 pg/mL. Insler scores were ≥5 at least once in 102/117 (87%) of participants, and ovulation occurred at least once in 81/117 (69%). Sixty participants (51%) had at least one ovulation following an Insler score ≥5; this occurred most frequently among higher-BMI participants using the lower-dose patch (19/25, 76%).

Conclusions: Women using two investigational LNG patches did not achieve consistent concentrations of LNG >180 pg/mL, an efficacy benchmark established in other studies with LNG implants, and they experienced high rates of ovulation as well as cervical mucus scores not supportive of high contraceptive efficacy.

Implications: The novel LNG-only patches in this study may not adequately decrease pregnancy risk, particularly for higher-BMI women. Future studies of LNG-only contraceptive patches will need to employ higher LNG doses and assess the acceptability and safety of such dosing.

Keywords: Cervical mucus; Contraceptive patch; Levonorgestrel; Ovulation suppression; Pharmacodynamics.