The PK/PD Relationship of Ethinyl Estradiol and Unscheduled Bleeding or Spotting for an Ascending-dose, Estrogen/Progestin Combination Oral Contraceptive (OC)

Authors: Darwish M, Bond M, Ricciotti N, Hsieh J, Walawander CA, Grasela TH
Conference: Society for Gynecologic Investigation (SGI)
Keywords: gynecology, hormones, PK/PD, urology
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Abstract

Introduction: The estrogen component of OCs 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 OC (ADER) has been developed to provide 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. This analysis characterizes the profile of US/UB with ADER.

Methods: Data were combined from several clinical studies in which ADER (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), constant-dose EE/LNG-OC (CDS; LNG 150 mcg/EE 30 mcg Days 1-84; 10 mcg EE Days 85-91), or lowconstant- dose EE/LNG-OC (CDloS; LNG 100 mcg/EE 20 mcg Days 1-84; 10 mcg EE alone Days 85-91) were administered to non-pregnant women of childbearing age.

Results: The % of subjects on ADER experiencing UB/US increased over the initial 42 days and then stabilized for the remainder of the cycle (Days 43-84). Analysis of the % of patients experiencing UB/US over time consistently shows less UB/US during the second half of each cycle (Days 43-84) with ADER vs CDS and CDloS (observed in each extended cycle studied up to 4). During the initial 42-day period, the PK model predicted a steady-state trough EE plasma concentration of 9.67 pg/mL during dosing with EE 20 mcg. Days 43-63, 25 mcg EE begins the UB stabilization period, which coincides with a predicted increase in trough EE plasma concentration to 12.08 pg/mL. A second EE dose increase to 30 mcg, Days 64-84, is predicted to result in a trough EE plasma concentration of 14.50 pg/mL. Conversely, the predicted EE trough concentrations with CDS and CDloS remained constant at 16.97 and 9.67 pg/mL through Day 84.

Conclusions: The gradual increase in dose of EE in ADER during Days 43-84 of the 91-day treatment cycle resulted in increasing steady-state EE plasma concentrations that correlated with a lower percentage of subjects experiencing UB/US compared to the sustained constant plasma levels of EE in CDS or CDloS.

Society for Gynecologic Investigation (SGI), Orlando, Florida, March 2013

By Mona Darwish, PhD; Mary Bond, MS, MBA; Nancy Ricciotti, MSN; Jennifer Hsieh, MS; Cynthia A. Walawander, MA; Thaddeus H. Grasela, PharmD, PhD