Single‐ and multiple‐dose escalation study to assess pharmacokinetics, pharmacodynamics and safety of oral esaxerenone in healthy Japanese subjects

Kato, Manabu; Furuie, Hidetoshi; Shimizu, Takako; Miyazaki, A.; Kobayashi, Fumiaki; Ishizuka, Hitoshi

doi:10.1111/bcp.13616

Cited by 43 publications

(66 citation statements)

References 18 publications

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“…This was a 12-week trial on the basis of previous trials of eplerenone and spironolactone to ensure sufficient time for the efficacy evaluation to be performed after the decrease in UACR had reached a steady state (19,20). The highest dose (5 mg/d) was on the basis of the safety data from a phase 2a study (unpublished data) and a phase 1 study in healthy adults (18).…”

Section: Methodsmentioning

confidence: 99%

“…Pharmacokinetic analysis included the assessment of trough plasma esaxerenone concentrations, and samples were collected on weeks 4 and 12. These plasma samples were analyzed using liquid chromatography-tandem mass spectrometry as described previously (18).…”

Section: End Pointsmentioning

confidence: 99%

“…Esaxerenone (CS-3150; Daiichi-Sankyo), a nonsteroidal mineralocorticoid receptor blocker, showed kidney protective effects in preclinical studies and may be added to existing treatments for patients with diabetic kidney disease (16,17). In a phase 1 study, the safety of a single dose and multiple doses of esaxerenone was confirmed in healthy Japanese subjects (18). The objective of this study was to evaluate the dose-response, efficacy, and safety of esaxerenone and determine the optimal dose for decreasing albuminuria in participants with type 2 diabetes mellitus and microalbuminuria.…”

Section: Introductionmentioning

confidence: 99%

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Efficacy and Safety of Esaxerenone (CS-3150) for the Treatment of Type 2 Diabetes with Microalbuminuria

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Shikata

Nangaku

et al. 2019

CJASN

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Background and objectives The progression of kidney disease in some patients with type 2 diabetes mellitus may not be adequately suppressed by renin-angiotensin system inhibitors. Esaxerenone (CS-3150) is a nonsteroidal mineralocorticoid receptor blocker that has shown kidney protective effects in preclinical studies, and it is a potential add-on therapy to treat diabetic kidney disease. This phase 2 study evaluated the efficacy and safety of esaxerenone in Japanese patients with type 2 diabetes mellitus and microalbuminuria.Design, setting, participants, & measurements This multicenter, randomized, double-blind, placebo-controlled trial enrolled 365 hypertensive or normotensive patients with type 2 diabetes mellitus and microalbuminuria (urinary albumin-to-creatinine ratio $45 to ,300 mg/g creatinine) treated with renin-angiotensin system inhibitor who had eGFR$30 ml/min per 1.73 m 2 . Participants were randomized to receive 0.625, 1.25, 2.5, or 5 mg/d esaxerenone or placebo for 12 weeks. The primary end point was the change in urinary albumin-tocreatinine ratio from baseline to week 12 (with last observation carried forward).Results Esaxerenone treatment at 1.25, 2.5, and 5 mg/d significantly reduced urinary albumin-to-creatinine ratio by the end of treatment (38%, 50%, and 56%, respectively) compared with placebo (7%; all P,0.001). The urinary albumin-to-creatinine ratio remission rate (defined as urinary albumin-to-creatinine ratio ,30 mg/g creatinine at the end of treatment and $30% decrease from baseline) was 21% in the 2.5-and 5-mg/d groups versus 3% for placebo (both P,0.05). Adverse events occurred slightly more frequently with esaxerenone versus placebo, but the frequencies of drug-related adverse events and discontinuation rates were similar in the placebo and the 0.625-, 1.25-, and 2.5-mg/d groups. Drug-related adverse events and treatment discontinuations were marginally higher in the 5-mg/d group. The most common drug-related adverse event was hyperkalemia, which was dose proportional.Conclusions Adding esaxerenone at 1.25, 2.5, and 5 mg/d for 12 weeks to an ongoing renin-angiotensin system inhibitor significantly reduces urinary albumin-to-creatinine ratio in patients with type 2 diabetes mellitus and microalbuminuria.

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Section: Methodsmentioning

confidence: 99%

Section: End Pointsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Efficacy and Safety of Esaxerenone (CS-3150) for the Treatment of Type 2 Diabetes with Microalbuminuria

Ito

Shikata

Nangaku

et al. 2019

CJASN

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“…After the oral administration of [ 14 C]esaxerenone, the major elimination pathway was oxidation in rats, and oxidation and glucuronidation in monkeys, and the radioactivity was excreted mainly in the feces (Yamada et al, 2017). In phase 1 studies, the exposure of esaxerenone after single (5-200 mg/d) and multiple (10-100 mg/d) doses was generally proportional to the dose (Kato et al, 2018). The times to reach the maximum plasma concentration (T max ) and t 1/2 after single oral administration were approximately 3 and 20 hours, respectively, and did not change across dose levels (Kato et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…In phase 1 studies, the exposure of esaxerenone after single (5-200 mg/d) and multiple (10-100 mg/d) doses was generally proportional to the dose (Kato et al, 2018). The times to reach the maximum plasma concentration (T max ) and t 1/2 after single oral administration were approximately 3 and 20 hours, respectively, and did not change across dose levels (Kato et al, 2018). The t 1/2 appears to be suitable for once-daily dosing because efficacy is expected to be sustained throughout the day.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics, Metabolism, and Excretion of [¹⁴C]Esaxerenone, a Novel Mineralocorticoid Receptor Blocker in Humans

et al. 2018

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Esaxerenone (CS-3150) is a novel, nonsteroidal, selective mineralocorticoid receptor blocker. The absorption, metabolism, distribution, and excretion of esaxerenone were assessed in in vitro studies and in a clinical study, where [ 14 C]esaxerenone (150 mCi/ 20 mg) was administered orally to six healthy male subjects. The plasma concentrations of esaxerenone and its metabolites (M4, M11, and M1) were measured using liquid chromatographytandem mass spectrometry. The recovery of radioactivity was 92.5%, with 38.5% and 54.0% excreted in the urine and feces, respectively. The half-life of radioactivity in blood and plasma was approximately 30 hours, similar to that of the unchanged form in plasma. The blood-to-plasma ratio was 0.628, demonstrating low partitioning to blood components. In plasma, esaxerenone was the most abundant moiety (40.8%), followed by O-glucuronide (21.4%; M4), acyl-glucuronide of amide-bond hydrolysate (8.0%; M11), and the deshydroxyethyl form (1.7%; M1). In vitro studies showed that esaxerenone was a substrate of CYP3A and multiple UDPglucuronosyltransferase isoforms. Oxidation contributed approximately 30% to its clearance, as indicated by the excretion ratio of oxidized metabolites into urine and feces. Caco-2 studies showed that esaxerenone was a substrate of P-glycoprotein and breast cancer resistance protein; however, the excretion ratios of the unchanged form in the feces and urine were 18.7% and 1.6%, respectively, indicating that these transporters were not important for the absorption and elimination of esaxerenone. Low urinary excretion of esaxerenone suggested that the plasma exposure of esaxerenone was not affected by renal dysfunction. Multiple elimination pathways including oxidation, glucuronidation, and hydrolysis, and the low contribution of transporters, indicated limited drug-drug interaction potential. https://doi.org/10.1124/dmd.118.084897.s This article has supplemental material available at dmd.aspetjournals.org.

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Esaxerenone (Minnebro), An Oral, Non‐steroidal, Selective Mineralocorticoid Receptor Blocker for the Treatment of Essential Hypertension

Ambhaikar¹

2022

Current Drug Synthesis

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Single‐ and multiple‐dose escalation study to assess pharmacokinetics, pharmacodynamics and safety of oral esaxerenone in healthy Japanese subjects

Cited by 43 publications

References 18 publications

Efficacy and Safety of Esaxerenone (CS-3150) for the Treatment of Type 2 Diabetes with Microalbuminuria

Efficacy and Safety of Esaxerenone (CS-3150) for the Treatment of Type 2 Diabetes with Microalbuminuria

Pharmacokinetics, Metabolism, and Excretion of [¹⁴C]Esaxerenone, a Novel Mineralocorticoid Receptor Blocker in Humans

Esaxerenone (Minnebro), An Oral, Non‐steroidal, Selective Mineralocorticoid Receptor Blocker for the Treatment of Essential Hypertension

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Single‐ and multiple‐dose escalation study to assess pharmacokinetics, pharmacodynamics and safety of oral esaxerenone in healthy Japanese subjects

Cited by 43 publications

References 18 publications

Efficacy and Safety of Esaxerenone (CS-3150) for the Treatment of Type 2 Diabetes with Microalbuminuria

Efficacy and Safety of Esaxerenone (CS-3150) for the Treatment of Type 2 Diabetes with Microalbuminuria

Pharmacokinetics, Metabolism, and Excretion of [14C]Esaxerenone, a Novel Mineralocorticoid Receptor Blocker in Humans

Esaxerenone (Minnebro), An Oral, Non‐steroidal, Selective Mineralocorticoid Receptor Blocker for the Treatment of Essential Hypertension

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Pharmacokinetics, Metabolism, and Excretion of [¹⁴C]Esaxerenone, a Novel Mineralocorticoid Receptor Blocker in Humans