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. 2018 Dec;104(6):1229-1239.
doi: 10.1002/cpt.1085. Epub 2018 Apr 27.

Risk-Benefit Assessment of Ethinylestradiol Using a Physiologically Based Pharmacokinetic Modeling Approach

Udoamaka Ezuruike  1 , Helen Humphries  1 , Maurice Dickins  1 , Sibylle Neuhoff  1 , Iain Gardner  1 , Karen Rowland Yeo  1
Affiliations

Risk-Benefit Assessment of Ethinylestradiol Using a Physiologically Based Pharmacokinetic Modeling Approach

Udoamaka Ezuruike et al. Clin Pharmacol Ther. 2018 Dec.

Abstract

Current formulations of combined oral contraceptives (COC) containing ethinylestradiol (EE) have ≤35 μg due to increased risks of cardiovascular diseases (CVD) with higher doses of EE. Low-dose formulations however, have resulted in increased incidences of breakthrough bleeding and contraceptive failure, particularly when coadministered with inducers of cytochrome P450 enzymes (CYP). The developed physiologically based pharmacokinetic model quantitatively predicted the effect of CYP3A4 inhibition and induction on the pharmacokinetics of EE. The predicted Cmax and AUC ratios when coadministered with voriconazole, fluconazole, rifampicin, and carbamazepine were within 1.25 of the observed data. Based on published clinical data, an AUCss value of 1,000 pg/ml.h was selected as the threshold for breakthrough bleeding. Prospective application of the model in simulations of different doses of EE (20 μg, 35 μg, and 50 μg) identified percentages of the population at risk of breakthrough bleeding alone and with varying degrees of CYP modulation.

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Figures

Figure 1
Figure 1
Workflow of EE model development. The base model was developed using a mixture of a bottom‐up and top‐down (i.e., a middle‐out) approach incorporating physicochemical data, in vitro metabolism data, and data from an intravenous study. The estimated fmCYP from in vitro data was refined using a clinical DDI study with ketoconazole. The refined model was independently verified using clinical studies with other CYP inhibitors and inducers. Simulated and observed mean plasma concentration–time profile of EE are shown above after (a) multiple oral doses of 35 μg q.d. administered alone for 21 days; (b) multiple oral doses of 35 μg q.d. administered alone for 21 days and in the presence of voriconazole (strong CYP3A4 inhibitor) given as 400 mg b.d. on Day 18 followed by 200 mg b.d. given on Days 19–21; and (c) multiple oral doses of 35 μg q.d. administered alone for 7 days and In the presence of rifampicin (strong CYP3A4 inducer) given as 600 g q.d. on Days 12–21. The dark lines represent the mean plasma concentration–time profiles, while the gray lines represent the predictions from individual trials of (a) 10 trials × 10 female HV, 20–50 years; (b) 10 trials × 16 female HV, 18–40 years; and (c) 10 trials × 12 female HV, 23–44 years. The black dashed lines represent the mean plasma concentration–time profiles of simulations done in the presence of a perpetrator drug, while the gray dashed lines represent the predictions from individual trials of simulations done in the presence of a perpetrator drug. The different circles in (a) are data points from observed data: open circles,48 purple circles,28 red circles,35 black circles,49 blue circles,24 green circles,26 and brown circles25; while the data points in (b,c) are from references 26 and 29, respectively. [Color figure can be viewed at http://cpt-journal.com]
Figure 2
Figure 2
Simulated (black line) and observed (data points) mean plasma concentration–time profiles of EE after a single dose of 50 μg administered intravenously on a linear (a) and logarithmic scale (b); and administered orally on a linear (c) and logarithmic scale (d). The gray lines represent predictions from individual trials (10 trials × 6 female HV; 21–23 years) for the i.v. dosing; and (10 trials × 10 female HV; 20–50 years) for the oral dosing. Dashed lines represent the 5th and 95th percentiles. Observed data were obtained from Ref. 14 (black circles) and Ref. 50 (open circles).
Figure 3
Figure 3
(a) A schematic of the disposition of ethinylestradiol after oral administration based on published data, showing the fraction absorbed (fa), fraction extracted in the gut during first‐pass metabolism (EG), and the fraction of the drug that reaches the systemic circulation (F); as well as the different routes of systemic metabolism of the drug; and (b) predicted mean contribution of metabolic and renal clearance to the systemic elimination of ethinylestradiol using the optimized PBPK model (10 trials × 10 female HV; 20–50 years).
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