SUN-440 Evaluation of Potential Drug-Drug Interactions with Crinecerfont

Abstract Disclosure: R.J. Auchus: Contracted Research for Neurocrine Biosciences/Neurocrine UK, LTD, Spruce Biosciences, Corcept Therapeutics, Crinetics Pharmaceuticals, Consultant for Quest Diagnostics, Corcept Therapeutics, Xeris Pharmaceuticals, Crinetics Pharmaceuticals, Novo Nordisk, Neurocrine Biosciences/Neurocrine UK, LTD, Consultant for Recordati Rare Diseases, Crinetics Pharmaceuticals, Inc, Camurus, Xeris Pharmaceuticals, Inc; Educational speaking engagement with Recordati Rare Diseases, Contracted Research for Recordati Rare Diseases, Adrenas Therapeutics, and Mineralys Pharmaceuticals. K. Sarafoglou: Research support from Office of Orphan Products Development of the Food and Drug Administration (R01FDR0006100), NIH-NCATS (UL1TR002494), NIH NINDS (U54NS115198), Neurocrine Biosciences, Research support from Spruce Biosciences, Crinetics Pharmaceuticals, Adrenas Therapeutics, Alexion Pharmaceuticals, BioMarin Pharmaceuticals. M.E. Geffner: Research support from Ascendis, Diurnal, Neurocrine Biosciences, Novo Nordisk, Pfizer, and Spruce Biosciences, Advisory board / consultant for Adrenas Therapeutics, Ascendis, Eton Pharmaceuticals, Neurocrine Biosciences, Novo Nordisk, Pfizer, Spruce Biosciences, and Theratechnologies, Inc., Serves as an adjudication committee member for ICON Clinical Research, LLC/Aeterna Zentaris; and receives royalties from McGraw-Hill and UpToDate. R. Pivonello: Research funding from Corcept Therapeutics, Neurocrine Biosciences, Recordati AG, Spruce Bioscience and Xeris Pharmaceuticals (Strongbridge Biopharma), Consultant for Corcept Therapeutics, Crinetics Pharmaceuticals, H Lundbeck A/S and Recordati Rare Diseases. C. Simeoli: Consultant for Neurocrine UK Ltd, and Recordati Rare diseases. M. Clemente: None. G. Loewen: Former full-time employee of Neurocrine Biosciences, Inc. E. Roberts: Full-time employee of Neurocrine Biosciences, Inc. R.H. Farber: Full-time employee of Neurocrine Biosciences, Inc. J.L. Chan: Full-time employee of Neurocrine Biosciences, Inc. J. Sturgeon: Full-time employee of Neurocrine Biosciences, Inc. E. Smith: Full-time employee of Neurocrine Biosciences, Inc. N. Giri: Full-time employee of Neurocrine Biosciences, Inc.. Background: Crinecerfont, a corticotropin-releasing factor type 1 receptor (CRF1) antagonist, is a first-in-class medication that is FDA-approved for adjunctive treatment to glucocorticoid replacement to control androgens in patients 4 years of age or older with classic congenital adrenal hyperplasia. Objective: To assess the potential for clinical drug-drug interactions between crinecerfont and co-medications to inform clinical use. Methods: Using medications that are typical for evaluating potential drug-drug interactions, phase 1 clinical studies were conducted in healthy volunteers to assess the impact of co-medications on crinecerfont pharmacokinetics (PK) or the impact of crinecerfont on the PK of co-medications. Study 1 (N=16) evaluated the PK of crinecerfont 50 mg with (Test) or without (Reference) ketoconazole 400 mg (strong CYP3A4 inhibitor). Study 2 (N=16) evaluated the PK of crinecerfont 100 mg with (Test) or without (Reference) rifampin 600 mg (strong CYP3A4 inducer). Study 3 (N=25) evaluated the PK of an oral contraceptive (ethinylestradiol/levonorgestrel 30/150 µg) with (Test) or without (Reference) crinecerfont 100 mg. PK parameters, including maximum concentration (Cmax) and area under the concentration-time curve (AUC), were derived using non-compartmental methods. Geometric mean ratios (GMRs) with 90% confidence intervals (90% CI) of the Test to Reference were calculated using log-transformed data. Results: Coadministration of ketoconazole (strong CYP3A4 inhibitor) resulted in GMR [90% CI] of 125% [107-147%] and 145% [129-164%] for crinecerfont Cmax and AUCinf, respectively. Coadministration of rifampin (strong CYP3A4 inducer) resulted in GMR [90% CI] of 77.1% [66.6-89.4%] and 37.8% [33.3-42.9%] for crinecerfont Cmax and AUCinf, respectively. For the oral contraceptive, crinecerfont coadministration resulted in GMR [90% CI] of 106% [101-112%] and 103% [98-108%] for ethinylestradiol Cmax and AUC24h respectively. Crinecerfont coadministration resulted in (GMR [90% CI] of 106% [100-112%] and 105% [100-110%] for levonorgestrel Cmax and AUC24h, respectively. Conclusion: Given the safety profile of crinecerfont, the increase in crinecerfont exposure with ketoconazole was not considered clinically relevant, and no dose adjustments are necessary when administering crinecerfont with CYP3A4 inhibitors. Decreased crinecerfont exposure with rifampin might reduce the efficacy of crinecerfont. Thus, if taken with a strong CYP3A4 inducer, the morning and evening doses of crinecerfont should be increased 2-fold. If taken with a moderate CYP3A4 inducer, increasing only the evening dose 2-fold is recommended. The effects of crinecerfont on oral contraceptive exposures were not considered clinically relevant, indicating that crinecerfont does not significantly affect oral contraceptive metabolism. Presentation: Sunday, July 13, 2025