Pharmacokinetic Profile of an Ascending-Dose, Estrogen/Progestin Combination Oral Contraceptive
Introduction: The estrogen component of oral contraceptives provides stability to the endometrium so that irregular shedding and unwanted breakthrough bleeding are minimized. An ascending-dose, extended-regimen ethinyl estradiol/levonorgestrel (EE/LNG) combination oral contraceptive (ADER) has been developed with the intent of providing better protection against unscheduled bleeding (UB) or spotting (US). It is hypothesized that gradual increases in EE may be more effective in preventing UB/US than sustained low levels of estrogen. The stepwise increase may also be better suited to preventing these events as compared to persistent high levels of EE which may desensitize the estrogen receptors. The current analysis characterizes the pharmacokinetics of EE following administration of ADER.
Methods: A population pharmacokinetic (PK) model was used to predict EE plasma concentrations over time following administration of ADER to non-pregnant women of childbearing age. ADER consists of the following: LNG, 150 mcg for 84 days with EE, 20 mcg Days 1-42; 25 mcg Days 43-63; 30 mcg Days 64-84; 10 mcg EE Days 85-91.
Results: The model-predicted plasma concentration-time profiles demonstrated that there is a step-wise increase in systemic exposure to EE with increase in dose over the first 84 days of the cycle as assessed by steady-state Cmax, Cmin, and AUC prior to each EE dose change. PK profiles of ADER on the final day prior to each EE dose change showed that Cmax rose from 55.77 pg/mL at day 42 to 69.72 pg/mL at day 63 and 83.66 pg/mL at Day 84 while Cmin increased from 9.67, to 12.08, and 14.5 pg/mL at Days 42, 63, and 84, respectively. These increases are followed by lower concentrations of EE during the 7-day period of low-dose estrogen (10 mcg) which replaces the typical hormone-free interval at the end of the cycle. Predicted Cmax and Cmin values during the final 7 days of the cycle were 27.92 pg/mL and 4.85 pg/mL, respectively.
Conclusions: The increasing dose of EE in ADER results in a step-wise increase in systemic exposure to EE over the 84-day active-treatment period followed by lower EE concentrations. This changing concentration of EE may provide better protection against UB/US than sustained EE doses.
Society for Gynecologic Investigation (SGI) Orlando, FL, March 2013
By Mona Darwish, PhD; Mary Bond, MS, MBA; Nancy Ricciotti, MSN; Jennifer Hsieh, MS; Jill Fiedler-Kelly, MS; Thaddeus H. Grasela, PharmD, PhD