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Pharmacokinetics, tolerability and cycle control of three transdermal contraceptive delivery systems containing different doses of ethinylestradiol and levonorgestrel

Abstract Background: The only available contraceptive patch, Ortho Evra®, delivers a relatively high dose of estrogen. Materials and methods: Three transdermal contraceptive delivery systems (TCDS) containing low doses of ethinylestradiol (EE) and levonorgestrel (LNG) were evaluated in two open-label randomized trials. In a phase 1, two-period, cross-over trial, AG200-12.5 and AG200LE were compared with a 150 μg LNG/30 μg EE oral contraceptive (OC) (Levlen®) in 39 women. In a phase 2, parallel-group, multicenter, three-cycle study, AG200LE, AG200-12.5 and a higher-dose formulation, AG200-15, were evaluated in 123 women. Results: In Study 1, mean steady-state plasma concentrations (Css, pg/mL) for the TCDS were 17 pg/mL to 26 pg/mL for EE and 1117 pg/mL to 1505 pg/mL for LNG (for AG200LE and AG200-12.5 respectively). Maximum concentration (Cmax) and Css for both analytes were significantly lower than for Levlen. In both studies, the Css levels for EE and LNG in all groups were within the ranges reported for low-dose OCs. Cycle control for AG200-15, assessed by breakthrough bleeding and spotting episodes as well as number of days of unscheduled bleeding and/or spotting, was similar to that reported for low-dose OCs. Most adverse events were considered mild to moderate in intensity. The incidence of patches falling off was <2%. Conclusions: All three patches exhibited excellent safety and wearability profiles while maintaining plasma drug levels required for ovulation suppression and adequate cycle control. A slight increase in the EE dose in AG200-15 still places this TCDS within the range of low-dose OCs, with EE exposure much lower than reported for Ortho Evra. AG200-15 was selected for further testing in phase 3 studies.