Characterisation of the pharmacokinetics of ethinylestradiol and drospirenone in extended-cycle regimens: population pharmacokinetic analysis from a randomised Phase III study

Abstract

Objectives: The primary objective of this analysis was to characterise the steady-state pharmacokinetics (PK) of ethinylestradiol (EE) and drospirenone (DRSP) in a randomised Phase III study that investigated the contraceptive efficacy and safety of three different regimens of EE 20 µg/DRSP 3 mg.

Methods: Non-linear mixed-effects modelling was used to develop population PK models for EE and DRSP. EE and DRSP serum concentrations were determined in blood samples obtained from approximately 1100 healthy young women on two occasions during the first cycle (Week 3) and after 6 months (Week 27) of EE 20 µg/DRSP 3 mg use. EE 20 µg/DRSP 3 mg was administered as a flexible extended regimen [24-120 days' active hormonal intake followed by 4 days with no tablet intake (tablet-free interval)], a conventional 28-day cyclic regimen (24 days' active hormonal intake followed by 4 days of placebo tablets) or a fixed extended regimen (120 days' uninterrupted active hormonal intake followed by a 4-day tablet-free interval) over 1 year.

Results: The population PK of EE and DRSP in this population were successfully described using the developed population models. All three regimens led to similar steady-state drug exposure during long-term treatment. Only minor changes (≤ 8%) in the steady-state PK of EE and DRSP were observed between Week 3 and Week 27 of an extended regimen. Body weight (BW) and age had a small, statistically significant impact on the PK of EE and DRSP (BW only) in a covariate analysis, however, these changes were not considered to be clinically relevant.

Conclusions: Extending the established 24/4-day regimen of EE 20 µg/DRSP 3 mg does not change the known steady-state PK of EE and DRSP, suggesting that the clinical efficacy is also similar. This is in line with the published clinical results from this study.

Figures

Figure 1

(A) Observed ethinylestradiol (EE) and drospirenone (DRSP) serum concentrations and (B) final models of EE and DRSP for population predicted (lines) and observed (circles) concentrations in young healthy women on different EE 20 µg/DRSP 3 mg regimens. In A, black circles: flexible extended regimen with management of intracyclic (breakthrough) bleeding (flexibleMIB; 24–120/4); dark grey triangles: fixed extended regimen (120/4); light grey quadrangles: conventional regimen (24/4). In B, Week 3, Days 15–21 of the first cycle with daily administration of EE 20 µg/DRSP 3 mg. Week 27: Days 15–21 of the seventh cycle in a 24/4 regimen, or Days 59–65 of the second cycle in a fixed extended regimen (120/4), or Week 27 in a flexible extended regimen (24–120/4). Database: 4218 EE and 4042 DRSP serum concentrations from 1109 and 1096 subjects. At both visits, two samples were taken from each subject 45–120 minutes apart.

Figure 2

Final models for ethinylestradiol (EE) and drospirenone (DRSP): visual predictive checks. Scatter = observed values; continuous line = predicted median; dashed line = predicted lower and upper limit of 90% of the predictions. Visit 3 = Week 3; Visit 5 = Week 27.

Figure 3

Impact of the covariates body weight (BW) and age on ethinylestradiol (EE) exposure (A) and covariate BW on drospirenone (DRSP) exposure (B) in comparison with the overall distribution of individual EE or DRSP area under drug concentration time curves from 0–24 hours at steady state (AUC0–24 h, ss) in the study population. The AUC range between the 5th and 95th percentiles is shown as bars across the whole study population. The vertical line indicates the AUC value of a typical subject of median age (24 years) and weight (62 kg). Numbers in parentheses of the bars labelled with the covariate name indicate the deviation of the AUC value from the typical subject's value for the subjects at the 5th and 95th percentiles of the covariate distribution.

Figure 4

Final models for ethinylestradiol (EE) and drospirenone (DRSP): distribution of the individual EE and DRSP exposure at steady state (AUC0–24 h, ss) by regimen. Group 1 = flexible extended regimen with management of intracyclic (breakthrough) bleeding (24–120/4); Group 2 = fixed extended regimen (120/4); Group 3 = conventional regimen (24/4). Black line with dot = median; box = range between 25th and 75th percentile; whiskers = 5th and 95th percentile.

Figure 5

Minimum and maximum drospirenone concentrations to be expected with the conventional regimen (24/4) and an extended flexible 72/4-day regimen (simulated data).