Relacorilant

Relacorilant is a reversible glucocorticoid receptor (GR) antagonist. In functional in vitro assays with the mineralocorticoid receptor, relacorilant showed no agonist or antagonist activity. In human cell-line derived xenograft models, relacorilant enhanced apoptosis and antitumor activity when administered with paclitaxel.

Cortisol binding to the GR is immunosuppressive, decreasing secretion of pro‑inflammatory cytokines. GR antagonism may indirectly activate the immune system; relacorilant inhibited the cortisol-induced reduction of tumor necrosis factor alpha and interferon gamma in stimulated peripheral blood mononuclear cells.

Exposure-Response Relationships

Relacorilant exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.

Cardiac Electrophysiology

At 3.8 times the mean maximal relacorilant concentration of the recommended dosage, clinically significant QTc interval prolongation was not observed.

Relacorilant pharmacokinetics were observed in adult patients at the approved recommended dosage and are presented as mean (CV%), unless otherwise specified. Relacorilant maximum concentration (C_max) is 720 (68%) ng/mL and systemic exposure (AUC) is 5,686 (84%) ng*h/mL following the third consecutive daily dose.

Absorption

Relacorilant median (min, max) time to maximum plasma concentration (T_max) is 2.5 hours (1.2, 5.5).

Effect of Food

Relacorilant C_max increased 1.7-fold, AUC increased 2-fold, and T_max was delayed 0.5 hours following administration with a low-fat meal (approximately 400 to 500 calories, 25% fat content).

Relacorilant C_max increased 1.9-fold, AUC increased 2.4-fold, and T_max was delayed 0.25 hours following administration with a high-fat meal (approximately 800 to 1,000 calories, 50% fat content).

Distribution

Relacorilant apparent volume of distribution (V_z/F) is 2490 (54%) L after a single 150 mg dose under fasted conditions. Protein binding of relacorilant in human plasma is >99% in vitro.

Elimination

Relacorilant terminal half-life is 27 (30%) hours with an apparent total clearance of 52 (69%) L/h under fasted conditions.

Metabolism

Relacorilant is primarily metabolized by cytosolic reductases and CYP3A. An active metabolite, CORT125295, with functional activity approximately 5-fold lower than relacorilant, represents 75% of the parent AUC.

Excretion

After a single oral dose of radiolabeled relacorilant 250 mg to healthy participants, about 73% (<1% unchanged) of the dose was recovered in feces and 17% (<2% unchanged) in urine.

Specific Populations

No clinically significant differences in the pharmacokinetics of relacorilant were observed based on age (26 to 85 years), body weight (35 to 128 kg), race (White [81%], Asian [9%]), ethnicity (Non-Hispanic [93%], Hispanic [7%]), CLcr 30 to <90 mL/min, or mild hepatic impairment (total bilirubin > ULN to ≤1.5 × ULN or AST > ULN and total bilirubin ≤ ULN).

The effect of CLcr <30 mL/min or end-stage renal disease undergoing hemodialysis or severe hepatic impairment (total bilirubin >3 to 10 × ULN and any AST) on the pharmacokinetics of relacorilant is unknown.

Patients with Hepatic Impairment

Relacorilant AUC increased 1.3-fold in participants with moderate hepatic impairment (Child-Pugh Class B).

Drug Interaction Studies

Clinical Studies

Nab-paclitaxel: Dose-normalized paclitaxel (CYP2C8 and CYP3A4 substrate) C_max increased 2-fold and dose-normalized AUC increased 1.7-fold following coadministration of nab-paclitaxel with relacorilant 150 mg.

No clinically significant differences in the pharmacokinetics of relacorilant were observed when given in combination with nab-paclitaxel.

Strong CYP3A Inhibitors: Relacorilant (300 mg once daily for 10 days under fasted conditions) steady state C_max increased 1.2-fold and steady state AUC increased 1.5-fold following coadministration of itraconazole (strong CYP3A inhibitor) 200 mg once daily for 10 days.

CYP3A Substrates: Midazolam (CYP3A substrate) C_max increased 3.1-fold and AUC increased 8.9-fold following coadministration of relacorilant 350 mg under fasted conditions (1.8 times the relacorilant exposure at the recommended dosage) once daily for 10 days.

CYP2C8 Substrates: Pioglitazone (CYP2C8 substrate) C_max decreased to 78% and AUC to 75% following coadministration of relacorilant 350 mg under fasted conditions (1.8 times the relacorilant exposure at the recommended dosage) once daily for 11 days.

Other Drugs: No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with relacorilant: metoprolol (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19), or dabigatran etexilate (P-gp).

In vitro Studies

CYP450 Enzymes: Relacorilant and CORT125295 are inducers of CYP1A2.

Transporter Systems: Relacorilant and CORT125295 are inhibitors of BCRP.