Drug-Drug Interactions of the Nonsteroidal Mineralocorticoid Receptor Antagonist Apararenone With Midazolam, Warfarin, and Digoxin: A Phase 1 Studies in Healthy Volunteers

Purpose: To characterize the clinical relevance of in vitro drug-drug interaction findings with apararenone (MT-3995), the effects of apararenone on the sensitive substrates of cytochrome P450 3A4 (midazolam) and 2C9 (warfarin), and P-glycoprotein (digoxin), were assessed through a series of studies conducted in healthy volunteers. Methods: Three studies were conducted in 56 healthy adults. Study 1 investigated the effects of the administration of apararenone with midazolam; apararenone was administered on days 2 (320 mg) and days 3-15 (20 mg/d), and midazolam 2 mg, on days 1 and 15. Study 2 investigated the effects of the administration of apararenone with warfarin; apararenone was administered on days 8-11 (40 mg/d) and days 12-27 (10 mg/d), and warfarin 25 mg, on days 1 and 21. Study 3 assessed the effects of the administration of apararenone with digoxin; apararenone was administered on days 11 (160 mg) and days 12-28 (10 mg/d), and digoxin 0.5 mg, on days 1 and 24. Pharmacokinetic parameters included C-max, AUC(0-t), and AUC(0-infinity). The safety profile was evaluated based on adverse events from spontaneous reports and clinical findings. Findings: After the administration of midazolam together with apararenone, compared with midazolam alone, the midazolam +/- apararenone treatment ratios (90% CIs) of the geometric least squares (LS) mean C-max, AUC(0-t), and AUC(0-infinity) values were 1.263 (1.147-1.392), 1.342 (1.220-1.477), and 1.370 (1.225-1.534), respectively. After the administration of warfarin +/- apararenone, the R-warfarin +/- apararenone treatment ratios (90% CIs) of the geometric LS mean C-max, AUC(0-t), and AUC(0-infinity) values were 1.008 (0.934-1.089), 1.078 (1.029-1.129), and 1.110 (1.056-1.166). Corresponding values for S-warfarin were 1.025 (0.941-1.117), 1.024 (0.979-1.071), and 1.031 (0.984-1.080). After the administration of digoxin +/- apararenone, the digoxin +/- apararenone treatment ratios (90% CIs) of the geometric LS mean C-max, AUC(0-t), and AUC(0-infinity) values were 0.929 (0.789-1.093), 0.894 (0.797-1.033), and 0.887 (0.805-0.977), respectively. Treatment-emergent adverse events were generally of mild to moderate intensity, and no serious adverse events of any kind were reported. (C) 2020 The Author(s). Published by Elsevier Inc.