Treatment of anemia associated with chronic kidney disease with the <scp>HIF</scp> prolyl hydroxylase inhibitor enarodustat: A review of the evidence

Fujikawa, Ryo; Nagao, Yuhei; Fujioka, Masaki; Akizawa, Tadao

doi:10.1111/1744-9987.13820

Cited by 8 publications

(14 citation statements)

References 47 publications

(134 reference statements)

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“…Thereafter, a dose adjustment was conducted every 4 weeks in the range of 1-8 mg/day of enarodustat until week 52. 15,16 In phase 3 study (MBA4-6), the efficacy and safety of enarodustat in ESA-naïve patients with HDD-CKD were assessed. Enarodustat was orally administered once daily at initial dose of 4 mg for 4 weeks.…”

Section: Methodsmentioning

confidence: 99%

“…From week 4 onward, the dose was adjusted every 4 weeks in the range of 1-8 mg/day until week 24. 16 Regarding the efficacy of enarodustat in phase 2b and phase 3 studies, the anemia correction effect (ie, Hb increase rate per week) and the Hb maintenance effect (ie, mean Hb level during the predefined evaluation period and achievement rate of mean Hb level within the target Hb range) were evaluated in ESA-naïve and ESAuntreated patients. The switching effect from ESAs to enarodustat (ie, change from baseline [CFB] in Hb level) and the Hb maintenance effect were evaluated in ESAtreated patients.…”

Section: Methodsmentioning

confidence: 99%

“…[10][11][12] The efficacy of enarodustat in the improvement of anemia in patients with CKD has been shown in phase 3 studies. [13][14][15][16] Enarodustat has been approved and marketed in Japan for the treatment of anemia in CKD. 17 Regarding ESAs, model-based analyses incorporating red blood cell (RBC) life span-based compartmental pharmacokinetic (PK) and pharmacodynamic (PD) model (eg, life span-based indirect response model or transit compartment model) have been conducted to understand the relationship between ESAs and hemoglobin (Hb) response.…”

mentioning

confidence: 99%

“…Thus, HIF‐PHIs are a new class of drugs that promote erythropoiesis mainly through increased production of endogenous erythropoietin (EPO) and modulation of iron metabolism 10–12 . The efficacy of enarodustat in the improvement of anemia in patients with CKD has been shown in phase 3 studies 13–16 . Enarodustat has been approved and marketed in Japan for the treatment of anemia in CKD 17…”

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confidence: 99%

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Evaluation of Hemoglobin Response to Treatment With Enarodustat Using Pharmacometric Approach in Japanese Anemic Patients With Chronic Kidney Disease

Naruhashi

Fujii

Yamada

et al. 2022

The Journal of Clinical Pharma

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Enarodustat (JTZ-951) is a hypoxia-inducible factor prolyl hydroxylase inhibitor that has been approved and marketed in Japan for patients with anemia with chronic kidney disease (CKD). The pharmacometric approach was applied to assess the relationship between plasma concentrations of enarodustat and hemoglobin (Hb) levels, and to provide information regarding the optimal use of enarodustat in clinical practice by simulations based on the pharmacokinetic and pharmacodynamic (PK/PD) model that was developed. The PK/PD data of enarodusat obtained from phase 2 and phase 3 studies in Japanese patients with CKD were well described by the models: a 1-compartment model with first-order absorption and elimination for PK, and a semimechanistic model based on transit compartment model for PD. Although several factors were identified as statistically significant covariates on the PK/PD of enarodustat, model-based simulations showed that none of them had clinically relevant impacts on the treatment effect (ie, Hb levels) of enarodustat. Hence, enarodustat treatment provides the stable Hb control with the initial dose (hemodialysis-dependent CKD: 4 mg/day, non-dialysis-dependent CKD: 2 mg/day) and maintenance dose (1-8 mg/day) to the patients with varied demographic characteristics.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Evaluation of Hemoglobin Response to Treatment With Enarodustat Using Pharmacometric Approach in Japanese Anemic Patients With Chronic Kidney Disease

Naruhashi

Fujii

Yamada

et al. 2022

The Journal of Clinical Pharma

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“…7,11 These treatments are expected to alleviate cardiovascular complications from high ESA doses and benefit ESA hyporesponsive patients. 12 This article aimed to review the mechanism of action and advantages of HIF-PHI therapy over ESA.…”

Section: Introductionmentioning

confidence: 99%

Anemia on Chronic Kidney Disease: The Role of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors

Riani

Widiana

2022

Intisari Sains Medis

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Anemia is one of the homeostatic abnormalities caused by chronic kidney disease and also frequently problem encountered in end-stage renal disease patients, regardless of the hemodialysis treatment. Anemia in chronic kidney disease significantly impairs kidney function, increases morbidity and mortality risk, and deteriorates the quality of life. Chronic kidney disease’s patients with anemia conditions are affected by numerous factors, including decreased production of endogenous erythropoietin, functional and absolute iron deficiency, and elevated hepcidin levels due to inflammation, particularly in hemodialysis patients. Treatment options for anemia in chronic kidney disease include exogenous erythropoietin and iron supplementation. A new mechanism known as the "hypoxia-sensing system" termed a mediator of erythropoietin synthesis, has been proposed to boost endogenous erythropoietin synthesis. The hypoxia-inducible factor activates specific gene expression and contributes to a physiological response to lower tissue oxygen levels. Chronic kidney disease’s patients who are contraindicated or are hyporesponsive to therapy with erythropoiesis-stimulating drugs may utilize this mechanism as an alternative.

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Evaluation of Drug–Drug Interaction Potential of Enarodustat (JTZ‐951) Using a Cytochrome P450 Probe Cocktail

Pai¹,

Yamada

Murata

2023

Clinical Pharm in Drug Dev

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The drug interaction potential of enarodustat (doses: 25, 50 mg) on the activity of cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4 was evaluated after once‐daily administration for 15 days in a phase 1 multiple‐ascending‐dose study in healthy subjects. Probe substrates specific for the enzymes, i.e., caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4), were administered orally as a cocktail with (day 15) and without (day −3) enarodustat. Drug interaction was based on geometric mean maximum plasma concentration (Cmax) and area under the plasma concentration‐time curve from the time of dosing to infinity (AUCinf) ratios (day 15/day −3) for CYP1A2, 2C9, 2C19, 2D6, 3A4, and urinary excretion of dextromethorphan metabolite dextrorphan for CYP2D6. At the 2 enarodustat doses, for caffeine, the geometric mean ratios (range) for Cmax and AUCinf were 0.99–1.06 and 1.61–1.63, respectively. The ratios for peak concentrations and total exposures were 0.98–1.07 and 0.71–1.78 for tolbutamide and omeprazole, respectively. For dextrorphan the Cmax and AUCinf ratios were 0.83–0.90 and 1.02–1.04, respectively. The mean dextrorphan cumulative amount excreted into the urine from the time of dosing to 24 hours values on day −3 and day 15 were 8.25 mg and 8.20 mg at the lower dose, and 9.40 mg and 9.51 mg at the higher dose. The ratios for midazolam Cmax and AUCinf were 1.42–1.63. Overall, there was a lack of enarodustat dose dependency regarding the geometric mean ratios and 90% confidence intervals and urinary excretion of dextrorphan. There were some cases where the 90% confidence intervals at the 2 enarodustat doses were outside the 0.80–1.25 range, but changes in the geometric mean ratios were all <2‐fold.

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Treatment of anemia associated with chronic kidney disease with the HIF prolyl hydroxylase inhibitor enarodustat: A review of the evidence

Cited by 8 publications

References 47 publications

Evaluation of Hemoglobin Response to Treatment With Enarodustat Using Pharmacometric Approach in Japanese Anemic Patients With Chronic Kidney Disease

Evaluation of Hemoglobin Response to Treatment With Enarodustat Using Pharmacometric Approach in Japanese Anemic Patients With Chronic Kidney Disease

Anemia on Chronic Kidney Disease: The Role of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors

Evaluation of Drug–Drug Interaction Potential of Enarodustat (JTZ‐951) Using a Cytochrome P450 Probe Cocktail

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