(T1330-02-12) A Phase 1, Open-Label, Drug-Drug Interaction Study Designed to Evaluate the Effect of Relacorilant on the Pharmacokinetics of the Sensitive P-gp Substrate Dabigatran Etexilate in Healthy Subjects

Purpose: Relacorilant (CORT125134) is an orally administered selective glucocorticoid receptor modulator without affinity for the progesterone receptor. Relacorilant is in development for the treatment of Cushing syndrome and for treatment of solid tumors in combination with chemotherapy or immunotherapy agents. In vitro, relacorilant exhibited inhibition of the efflux transporter P-glycoprotein (P-gp) in Caco-2 monolayer cellular assay. The current drug-drug interaction (DDI) study is designed to evaluate the effect of relacorilant on the PK of the sensitive P-gp substrate, dabigatran etexilate (DE) in healthy subjects.

Methods: Relacorilant was investigated as an inhibitor of P-gp mediated transport of probe substrate digoxin in vitro using a Caco-2 cell monolayer system. The inhibitory potential of relacorilant was evaluated over a concentration range of 0.01 to 10 µM to determine an IC₅₀ value. Relacorilant was investigated as an inhibitor of P-gp in vivo in a single center, open-label, non-randomized, single sequence, DDI study in fasted healthy male and female subjects, between the ages of 18 and 55 years with a body mass index of 19–32 kg/m² and body weight ≥50 kg (110 lb). Subjects were administered a single dose of DE 75 mg in the absence (Day 1) or presence (Day 12) of steady state plasma exposures of relacorilant 400 mg, which was administered once daily (QD) on Days 3 to 13. The 400 mg QD dose of relacorilant used in this study is the highest proposed clinical dose. The subjects remained on site until Day 14. Blood samples were collected at 0 (pre-dose) through 48 h post Day 1 and Day 12 DE dose administration. Plasma concentrations of free and total dabigatran were determined using a validated LC-MS/MS method. Pharmacokinetic parameters for free and total dabigatran were estimated using a Phoenix® noncompartmental analysis method and a formal statistical analysis was performed on exposure parameters. Safety was also assessed.

Results: Relacorilant inhibited P-gp in vitro with an IC₅₀ value of 1.3 µM. Doses of 75 mg DE and doses of 400 mg relacorilant administered QD were tolerated under the conditions of the study. Of the 30 subjects enrolled in the study, 24 completed the study, 5 withdrew consent due to a treatment emergent adverse event (TEAE) (upper abdominal pain in 4 subjects, nausea in 1 subject, and back pain in 1 subject), and 1 was withdrawn due to a TEAE which occurred prior to relacorilant dosing. The most commonly reported TEAEs considered to be related to relacorilant were upper abdominal pain, back pain, headache and nausea and were mild or moderate in severity. There was no meaningful change to the relacorilant safety profile when administered with DE, compared with relacorilant administered alone. No new safety findings were identified. Following a single oral dose of 75 mg DE alone in the absence of relacorilant (n= 30) on Day 1, adjusted geometric mean plasma exposures (based on C_max and AUC_0-inf) of free dabigatran were 76.5 ng/mL and 522 ng*h/mL, respectively; and of total dabigatran were 90.6 ng/mL and 629 ng*h/mL, respectively. Following a single oral dose of 75 mg DE and 400 mg QD dose of relacorilant (n= 24) on Day 12, the geometric mean plasma exposures (based on C_max and AUC_0-inf) of free dabigatran were 83.8 ng/mL and 503 ng*h/mL, respectively; and of total dabigatran were 111 ng/mL and 673 ng*h/mL, respectively. A formal primary statistical analysis showed that the geometric mean ratio (%GMR) and 90% confidence intervals (CI) of C_max and AUC_0-inf for free dabigatran, in the presence of relacorilant, were 113 (92.1-139) and 102 (84.2-124), respectively, compared to DE dosed alone in the absence of relacorilant. Similarly, the %GMR and CI of C_max and AUC_0-inf for total dabigatran, in the presence of relacorilant, were 124 (99.5-155) and 111 (91-135), respectively, compared to DE dosed alone in the absence of relacorilant.

Conclusion: Following a single oral dose of 75 mg DE, the free and total dabigatran plasma exposures (AUC_0-inf) were similar in the absence and presence of 400 mg QD relacorilant. There were small numeric increases in free and total dabigatran plasma C_max in the presence of relacorilant compared to dabigatran alone; these increases were not considered to be clinically relevant. Overall, 400 mg QD relacorilant had minimal-to-no impact on the free and total dabigatran plasma exposures, suggesting no dose adjustments are needed for P-gp substrates upon coadministration with relacorilant.