SAT-443 Osilodrostat Has No Clinically Relevant Effect on the Pharmacokinetic (PK) Profile of a Monophasic Oral Contraceptive in Healthy Females Receiving Cortisol Replacement Therapy

Abstract

Background: Osilodrostat, a potent oral 11β-hydroxylase inhibitor, is in Phase 3 development for endogenous Cushing’s syndrome (CS). As CS occurs mostly in females of childbearing age, it is important to determine the effect of osilodrostat on oral contraceptives (OCs). We report the effect of multiple osilodrostat doses on the PK profile of a single OC dose in healthy females on cortisol replacement. Methods: This Phase 1, single-center, open-label, three-period, drug-drug interaction study enrolled healthy, non-smoking females aged 18-50 y with regular menstrual cycles. A single OC dose, containing ethinyl estradiol (EES) 30 μg and levonorgestrel (LVG) 150 μg, was given on day (D) 1 of treatment period 1 (TP1; D1-7). In TP2 (D8-19), osilodrostat 30 mg twice daily was given with hydrocortisone 20 mg daily; a second OC dose was given on D15. Hydrocortisone was tapered/discontinued during TP3 (D20-28). Primary variable: AUC _last (area under curve from time 0 to last measurable concentration) and C _max (peak plasma concentration) of EES and LVG, calculated from a 120h OC PK profile on D1 and D15. Secondary endpoints: osilodrostat PK; safety/tolerability of OC and osilodrostat co-administration. Results: 24 subjects were enrolled (mean ± SD age, 37 ± 7 years; Caucasian, 96%). EES and LVG AUC _last were similar when OC was given with osilodrostat (n=19) vs alone (n=24) [geometric mean: EES, 541 vs 537 pg∙h/mL; LVG, 44900 vs 42300 pg∙h/mL]. Insignificant decreases in C _max were seen for OC with osilodrostat vs alone (geometric mean: EES, 51.6 vs 59.8 pg/mL; LVG, 3360 vs 3800 pg/mL). Apparent total clearance, t _½ (half-life) and t _max (time to C _max) were similar with and without osilodrostat for EES and LVG, except for a small increase in t _½ of LVG with osilodrostat (26.4 vs 22.9 h). For osilodrostat PK (n=19), geometric means for AUC _τ (AUC to end of dosing period at steady state) and C _max, and median t _max, were 1620 ng∙h/mL, 299 ng/mL, and 1.0 h, respectively. Most (92%) subjects received both OC doses; 83% completed osilodrostat treatment. At the end of TP3 (2 days after last hydrocortisone dose), 79% of subjects had ACTH-stimulated serum cortisol below the protocol-defined threshold, although all had normal unstimulated levels at study end; these results may be related to high osilodrostat doses, hydrocortisone supplementation, timing of first stimulation test after last hydrocortisone dose or another factor. Other common AEs: nausea (46%), headache and nasopharyngitis (both 38%). Four (17%) subjects discontinued due to: palpitations, n=1; throat tightness, n=1; asthenia and exhaustion, n=1; positive pregnancy test, n=1 (not confirmed by ultrasound). Conclusion: Concomitant treatment of osilodrostat (highest dose used in Phase 3 trials) with a single OC dose did not result in clinically relevant changes in OC PK parameters, suggesting that OC can be given with osilodrostat and provide adequate contraception.