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 Cmax, AUC0-t, and AUC0-∞. 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 Cmax, AUC0-t, and AUC0-∞ 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 Cmax, AUC0-t, and AUC0-∞ 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 Cmax, AUC0-t, and AUC0-∞ 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. IMPLICATIONS The findings from this analysis of data from healthy volunteers suggest minimal risk for potential drug-drug interactions between apararenone and other drugs that are likely to be used concurrently in patients. ClinicalTrials.gov identifier: NCT02531568.