New mineralocorticoid receptor antagonists: update on their use in chronic kidney disease and heart failure

Capelli, Irene; Gasperoni, Lorenzo; Ruggeri, Marco; Donati, Gabriele; Baraldi, Olga; Sorrenti, Giovanni; Caletti, Maria Turchese; Aiello, Valeria; Cianciolo, Giuseppe; Manna, Gaetano La

doi:10.1007/s40620-019-00600-7

Cited by 52 publications

(41 citation statements)

References 56 publications

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“…Although some drugs inhibit multiple UGTs in clinical use, there are relatively few UGT inhibitors. 4,5,23 Thus, clinically significant DDIs due to UGT inhibition are thought to rarely occur.…”

Section: Discussionmentioning

confidence: 99%

“…The MR antagonists currently used in clinical practice include a nonselective MR antagonist, spironolactone, and the selective MR antagonists eplerenone and esaxerenone, which are primarily used for the treatment of essential hypertension, heart failure, primary aldosteronism, and edema. 4,5 Furthermore, the possible clinical use of MR antagonists in the treatment of kidney diseases has been suggested from in vitro studies that have reported that MRs are also present in podocytes, 6 mesangial cells, 3 and fibroblasts, 7 indicating that MR antagonists may exert renoprotective activity by blocking direct injuries mediated by aldosterone on these cells.…”

Section: Introductionmentioning

confidence: 99%

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

Nakamura

Shimizu

Kawaguchi

2020

Clinical Therapeutics

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Nakamura

Shimizu

Kawaguchi

2020

Clinical Therapeutics

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“…Moreover, use of steroidal MRAs could induce severe hyperkalemia, gynecomastia, etc. (19) (20). Therefore, a new approach may be needed for CKD and diabetes patients for CV risk prevention and fewer safety concerns.…”

Section: Discussionmentioning

confidence: 99%

A retrospective cohort study of clinical characteristics, treatment patterns, and disease outcomes of chronic kidney disease in patients with diabetes using a Japanese claims database

Yamazaki

Yoshihara

et al. 2020

Preprint

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Objectives: The primary objective of this study was to characterize the clinical characteristics, treatment patterns, and clinical outcomes of chronic kidney disease (CKD) patients with diabetes, using a Japanese claims database and focusing on the use of mineralocorticoid receptor antagonists (MRAs) in this population in the real-world setting.Methods: This retrospective cohort study used the Medical Data Vision database, a large, electronic health records-based claims database in Japan. The observation period was a maximum of 8 years (from 1st April 2008 to 31st August 2016). The inclusion criteria were a claim with a diagnosis of diabetes (ICD-10: E10-E14), eGFR less than 60 mL/min/1.73 m2 at the index date, and use of any antiglycemic medications within 6 months prior to the index date or during the index month. Patients who had a claim for an MRA drug after the index date were identified as the MRA subcohort. This exploratory study investigated the burden of disease in patients with CKD and diabetes, including demographics, treatments, safety, and time-to-event analysis for renal and cardiovascular-related endpoints.Results: A total of 19,582 patients were included in the analysis, and 2,295 MRA patients were included in the subcohort. Renin-angiotensin-aldosterone system inhibitors were used at baseline by 52.3% in the overall cohort and 58.8% in the MRA subcohort. Cumulative incidences of hyperkalemia were 5.19% in the overall cohort and 7.63% in the MRA subcohort. Cox models showed that the 30–44 mL/min/1.73 m2 eGFR group had a significantly higher hazard of composite cardiovascular outcomes compared to the 45–59 mL/min/1.73 m2 group (HR, 1.22; 95% CI, 1.09–1.36).Conclusion: There are residual risks for hyperkalemia and renal and cardiovascular-related events in diabetic patients with CKD in the real-world setting in Japan, even after starting treatment with steroidal MRA drugs. The unmet needs and burden of disease should be considered in future treatments for CKD patients with diabetes.

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“…Aldosterone is a mineralocorticoid hormone with a well-known effect on the renal tubule leading to water retention and potassium reabsorption [ 97 ]. Other major effects of the hormone include the induction of proinflammatory activity, which leads to the progressive fibrotic damage of the target organs, heart and kidney.…”

Section: Common Drug Pipelines For Nafld/nash and Diabetic Nephropmentioning

confidence: 99%

Common Drug Pipelines for the Treatment of Diabetic Nephropathy and Hepatopathy: Can We Kill Two Birds with One Stone?

Sumida

Yoneda

Toyoda

et al. 2020

IJMS

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Type 2 diabetes (T2D) is associated with diabetic nephropathy as well as nonalcoholic steatohepatitis (NASH), which can be called “diabetic hepatopathy or diabetic liver disease”. NASH, a severe form of nonalcoholic fatty disease (NAFLD), can sometimes progress to cirrhosis, hepatocellular carcinoma and hepatic failure. T2D patients are at higher risk for liver-related mortality compared with the nondiabetic population. NAFLD is closely associated with chronic kidney disease (CKD) or diabetic nephropathy according to cross-sectional and longitudinal studies. Simultaneous kidney liver transplantation (SKLT) is dramatically increasing in the United States, because NASH-related cirrhosis often complicates end-stage renal disease. Growing evidence suggests that NAFLD and CKD share common pathogenetic mechanisms and potential therapeutic targets. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium–glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and diabetic nephropathy/CKD. There are no approved therapies for NASH, but a variety of drug pipelines are now under development. Several agents of them can also ameliorate diabetic nephropathy/CKD, including peroxisome proliferator-activated receptors agonists, apoptosis signaling kinase 1 inhibitor, nuclear factor-erythroid-2-related factor 2 activator, C-C chemokine receptor types 2/5 antagonist and nonsteroidal mineral corticoid receptor antagonist. This review focuses on common drug pipelines in the treatment of diabetic nephropathy and hepatopathy.

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New mineralocorticoid receptor antagonists: update on their use in chronic kidney disease and heart failure

Cited by 52 publications

References 56 publications

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

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

A retrospective cohort study of clinical characteristics, treatment patterns, and disease outcomes of chronic kidney disease in patients with diabetes using a Japanese claims database

Common Drug Pipelines for the Treatment of Diabetic Nephropathy and Hepatopathy: Can We Kill Two Birds with One Stone?

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