Estimating systemic exposure to ethinyl estradiol from an oral contraceptive

Abstract

Objectives This study was conducted to compare single-dose pharmacokinetics of ethinyl estradiol in an oral contraceptive to steady-state values, and to assess whether any simpler measures could provide an adequate proxy of the ‘gold standard’ 24-hour steady-state area-under-the-curve. Identifying a simple, less expensive, measure of systemic ethinyl estradiol exposure would be useful for larger studies designed to assess the relationship between an individual’s ethinyl estradiol exposure and her side effects. Study Design We conducted a 13 samples over 24 hours pharmacokinetic analysis on day 1 and day 21 of the first cycle of a monophasic oral contraceptive containing 30 mcg ethinyl estradiol and 150 mcg levonorgestrel in 17 non-obese healthy white women. We also conducted an abbreviated single dose 9-sample pharmacokinetic analysis after a month washout. Ethinyl estradiol was measured by liquid chromatography-tandem mass spectrometry. We compared results of full 13-sample steady-state pharmacokinetic analysis with results calculated using fewer samples (9 or 5) and following the single doses. We calculated Pearson correlation coefficients to evaluate the relationships between these estimates of systemic ethinyl estradiol exposure. Results The area-under-the-curve, maximum (Cmax), and 24-hour (C24) values were similar following the two single oral contraceptive doses (area-under-the-curve, r = 0.92). The steady-state 13-sample 24-hour area-under-the-curve was highly correlated with the average 9-sample area-under-the-curve after the two single doses (r = 0.81, p = 0.0002). This correlation remained the same if the number of samples was reduced to 4, taken at time 1, 2.5, 4 and 24 hours. The C24 at steady-state was highly correlated with the 24-hour steady-state area-under-the-curve (r = 0.92, p < 0.0001). The average of the C24 values following the two single doses was also quite highly correlated with the steady-state area-under-the-curve (r = 0.72, p = 0.0026). Conclusions Limited blood sampling, including results from two single doses, gave highly correlated estimates of an oral contraceptive user’s steady-state ethinyl estradiol exposure.

Clotting factor changes during the first cycle of oral contraceptive use

“…The level of EE2 in a tablet is, however, a poor indicator of a woman’s individual exposure due to individual differences in absorption and metabolism. Among the women in this study, all taking the same OC, we found the expected greater than two-fold range in steady state 24-hour EE2 exposure (488–1103 pg·h/mL) [25]. However, contrary to expectation, higher individual EE2 exposures were not associated with greater changes in either D-dimer or factor VIII activity.…”

“…D-dimer did not increase 24, 48 and 72 hours after taking the single pill after the 1-month washout period (data not shown). EE2-AUC21 varied from 488 to 1103 pg·h/Ml (data not shown, [25]); change in D-dimer concentration from baseline to OC21 was somewhat correlated with the individual systemic EE2-AUC21 (r = 0.36; 95% CI: −0.21, 0.75; p = 0.21). Figure 3 shows that this association was, however, largely due to the 2 participants whose D-dimer levels decreased substantially after entry to the study; removing these individuals reduced this correlation substantially (r = 0.15; 95% CI: −0.46, 0.67; p = 0.65).…”

“…Treatment began within 7 days of the start of menses [25]. Participants selected a particular time to take her daily OC, and we directly observed OC intake at this particular time on study visit days.…”

“…Participants sat quietly for 30 minutes prior to each blood draw using a 21 gauge butterfly needle in the antecubital vein. Each participant was admitted for 24 hours on days 1 and 21 to collect 14 timed samples for pharmacokinetic (PK) analyses, as previously described [25]. At each visit, participants answered questions about use of concomitant medications, caffeine/alcohol intake, and adverse events since the last visit.…”

“…We measured EE2 serum concentrations using liquid chromatography-tandem mass spectrometry and conducted standard PK analyses [25]. …”