Crinecerfont

Crinecerfont is a selective corticotropin-releasing factor (CRF) type 1 receptor antagonist. Crinecerfont blocks the binding of CRF to CRF type 1 receptors in the pituitary but not CRF type 2 receptors. Crinecerfont binding to CRF type 1 receptors inhibits adrenocorticotropic hormone (ACTH) secretion from the pituitary, thereby reducing ACTH-mediated adrenal androgen production.

Exposure-Response Relationships

Model based exposure-response analyses for adults and pediatric patients with CAH demonstrated that, within the studied exposures of crinecerfont in Phase 3 trials, relatively flat exposure-response relationships were observed for androstenedione reduction from baseline to Week 4 for both adults and pediatric patients and percent glucocorticoid daily dose reduction from baseline to Week 24 for adults and to Week 28 for pediatric patients.

Adrenocorticotropic Hormone (ACTH) Reduction

In 8 adults with classic CAH (NCT0352886) who received the recommended crinecerfont dosage for 2 weeks, the median percent reduction from baseline in ACTH was 62%.

In the Phase 3 clinical trials of adults and pediatric patients with classic CAH, administration of the recommended crinecerfont dosage for 4 weeks during the initial glucocorticoid stable period led to a reduction in ACTH levels.

In Study 1, the median percent reduction from baseline to Week 4 in ACTH was 65%.

In Study 2, the median percent reduction from baseline to Week 4 in ACTH was 72%.

Cardiac Electrophysiology

At a dose 4 times the maximum approved recommended dosage, crinecerfont does not prolong the QT interval to any clinically relevant extent.

Crinecerfont maximum plasma concentration (C_max) and area under the time concentration curve (AUC_{0-24 hours}) increases dose-proportionally over the approved recommended dosage range. Upon twice daily dosing, steady state conditions are achieved in approximately 7 days with an accumulation ratio of 1.4.

Absorption

Crinecerfont median time to reach C_max (T_max) is 4 hours following oral administration of crinecerfont.

No clinically significant differences in crinecerfont C_max or AUC were observed following administration of crinecerfont oral capsules and oral solution.

Steady state exposures for crinecerfont in adults and pediatric patients following oral administration of crinecerfont are presented in the following table.

Geometric Mean (CV%) for AUC_24,ss and C_max in Adults and Pediatric Patients with Classic Congenital Adrenal Hyperplasia Following Oral Administration of Crinecerfont:

CV%, coefficient of variation expressed as a percentage; bid, twice daily; steady-state exposure parameters are generated from simulation of 500 subjects based on population pharmacokinetic modeling and weight band appropriate formulation

Effect of Food

Following administration of crinecerfont capsule, crinecerfont C_max increased 4.9-fold and AUC increased 3.3-fold with a high-fat meal (800 to 1000 calories, 50% fat), compared to fasted conditions.

Following administration of crinecerfont oral solution, crinecerfont C_max increased 8.6-fold and AUC increased 8.3-fold with a high-fat meal (800 to 1000 calories, 50% fat), compared to fasted conditions.

Distribution

Mean apparent volume of distribution (CV%) of crinecerfont in adults with CAH is 852 L (31%). Crinecerfont plasma protein binding is greater than or equal to 99.9%.

Elimination

Crinecerfont's effective half-life is approximately 14 hours with a mean (CV%) apparent clearance of 3.5 L/h (37%).

Metabolism

Crinecerfont is metabolized primarily by CYP3A4 and to a lesser extent by CYP2B6 in vitro. Additionally, CYP2C8 and CYP2C19 may also have minor contributions to crinecerfont metabolism.

Excretion

Following a single oral 100 mg dose of radiolabeled crinecerfont, approximately 47.3% (2.7% as unchanged) of the dose was recovered in feces and 2% (amount as unchanged is undetectable) in urine.

Specific Populations

No clinically significant differences in the pharmacokinetics of crinecerfont were observed based on age (range: 5 to 54 years), sex (58.7% male), race (4.8% Asian, 9.7% Black, 77.5% White), mild to severe hepatic impairment (Child Pugh Class A to C), or mild to moderate renal impairment (estimated glomerular filtration rate: equal to or greater than 44 mL/min/1.73 m²; CKD-EPI 2009 formula for adults and bedside Schwartz formula for pediatric patients).

Crinecerfont has not been studied in patients with severe renal impairment or end-stage renal disease.

Drug Interaction Studies

Clinical Studies

Effect of Strong CYP3A4 Inducers on Crinecerfont: Crinecerfont C_max decreased by 23% and AUC decreased by 62% following concomitant use with rifampin (strong CYP3A4 inducer).

Effect of Strong CYP3A4 Inhibitors on Crinecerfont: Crinecerfont C_max and AUC increased by 25% and 45%, respectively, when used concomitantly with ketoconazole (strong CYP3A4 inhibitor).

Effect of Crinecerfont on CYP3A Substrates: No clinically significant differences in the pharmacokinetics of midazolam (CYP3A4 substrate) were observed when co-administered with crinecerfont. Concomitant use of crinecerfont did not affect the pharmacokinetics of oral contraceptives containing ethinyl estradiol and levonorgestrel.

In Vitro Studies

Cytochrome P450 Enzymes: Crinecerfont does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. Crinecerfont does not induce CYP2C8, CYP3A4, CYP1A2 and CYP2B6.

Transporter Systems: Crinecerfont does not inhibit P-glycoprotein (P-gp), breast cancer resistant protein (BCRP), bile salt export pump (BSEP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, multidrug and toxin extrusion protein (MATE)1, or MATE2-K.