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

Abstract

Purpose: To characterize the clinical relevance of in vitro drugedrug 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 3e15 (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 8e11 (40 mg/ d) and days 12e27 (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 12e28 (10 mg/d), and digoxin 0.5 mg, on days 1 and 24. Pharmacokinetic parameters included C max , AUC 0et , and AUC 0e∞. 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 0et , and AUC 0e∞ values were 1.263 (1.147e1.392), 1.342 (1.220e1.477), and 1.370 (1.225e1.534), respectively. After the administration of warfarin ± apararenone, the R-warfarin ± apararenone treatment ratios (90% CIs) of the geometric LS mean C max , AUC 0et , and AUC 0e∞ values were 1.008 (0.934e1.089), 1.078 (1.029e1.129), and 1.110 (1.056e1.166). Corresponding values for S-warfarin were 1.025 (0.941e1.117), 1.024 (0.979e1.071), and 1.031 (0.984e1.080). After the administration of digoxin ± apararenone, the digoxin ± apararenone treatment ratios (90% CIs) of the geometric LS mean C max , AUC 0et , and AUC 0e∞ values were 0.929 (0.789e1.093), 0.894 (0.797e1.033), and 0.887 (0.805e0.977), 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 drugedrug interactions between apararenone and other drugs that are likely to be used concurrently in patients. ClinicalTrials.gov identifier: NCT02531568.

Novel non‐steroidal mineralocorticoid receptor antagonists in cardiorenal disease

“…Unfortunately, no preclinical data on this compound are available. Recently, the results of two Phase I studies and a Phase II study have been published (Nakamura et al, 2020; Nakamura & Kawaguchi, 2021; Wada et al, 2021). In the introduction of these studies, some pharmacodynamic characteristics were described.…”

Discovery of Apararenone (MT-3995) as a Highly Selective, Potent, and Novel Nonsteroidal Mineralocorticoid Receptor Antagonist

“…The mixture was concentrated, and the residue was purified by silica gel flash column chromatography (n-hexane/AcOEt, 10:1 to 4:1) to give 38 (273 mg, 95%) as a pale yellow powder. 1 [1,4]oxazin-7-yl)methanesulfonamide (22). A mixture of 38 (200 mg, 0.662 mmol) and tin(II) chloride dihydrate (747 mg, 3.31 mmol) in EtOH (5 mL) was stirred at 80 °C for 5 h. Saturated aqueous NaHCO 3 and AcOEt were added under ice cooling, and the mixture was stirred at room temperature for 1 h, then insoluble materials were filtered off through Celite.…”

“…Therefore, in order to overcome these issues, the development of selective and potent MRAs is required, and extensive research has been conducted to identify novel nonsteroidal MRAs. , Compared with steroidal MRAs, nonsteroidal MRAs characterized by high MR selectivity are suggested to reduce the risk of hyperkalemia. − As a result of the compound optimization, some compounds have reached the stage of clinical development. − Notably, the most advanced compounds in this context are esaxerenone (CS-3150), which received marketing approval in Japan for the treatment of hypertension in 2019, finerenone (BAY94-8862), which was approved in the United States for the treatment of chronic kidney disease associated with type 2 diabetes in 2021, apararenone (MT-3995), KBP-5074, and AZD9977 (Figure ). In this article, we describe the design and discovery of 19 (apararenone: MT-3995), as well as the pharmacological profile of the said compound, which has completed phase II clinical trials for diabetic nephropathy and NASH, wherein it proved to be a highly selective and potent nonsteroidal MRA. − …”

Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease

“…) is a benzoxazinone derivative [104]. It is a long-acting, highly selective MRA [105,106]. Its major metabolite is 1118174, which has 1/50 of apararenone's affinity to bind to the MR.…”