Delving into the Latest Updates on Enarodustat with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Enarodustat (JAN), 恩那度司他

+ [5]

Target

HIF-PHs

Mechanism

HIF-PHs inhibitors(Hypoxia-inducible factor prolyl hydroxylase inhibitors)

Therapeutic Areas

Hemic and Lymphatic DiseasesUrogenital Diseases

Active Indication

chronic renal failure anemiaAnemia of renal disease

Inactive Indication-

Originator Organization

Japan Tobacco, Inc.

Active Organization

Shenzhen Salubris Pharmaceuticals Co., Ltd.

JW PHARMACEUTICAL Corp.

Japan Tobacco, Inc.

Inactive Organization

Akros Pharma, Inc.

Drug Highest PhaseApproved

First Approval Date

JP (25 Sep 2020),

Anemia of renal disease

Regulation-

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Structure

Molecular FormulaC17H16N4O4

InChIKeyNALAUGMPMIVAOW-UHFFFAOYSA-N

CAS Registry1262132-81-9

View All Structures (2)

主要目的：以深圳信立泰药业股份有限公司生产的恩那司他片为受试制剂（T制剂），以日本烟草产业株式会社生产的恩那司他片（商品名：ENAROY®）为参比制剂（R制剂），评价二者单次餐后给药的生物等效性。次要目的：观察两制剂在健康受试者中的安全性。

[Translation]

The primary objective was to evaluate the bioequivalence of single postprandial administration of Enarrostat Tablets produced by Shenzhen Xinlitai Pharmaceutical Co., Ltd. as the test preparation (T preparation) and Enarrostat Tablets (trade name: ENAROY®) produced by Japan Tobacco Co., Ltd. as the reference preparation (R preparation). The secondary objective was to observe the safety of the two preparations in healthy subjects.

Start Date09 Aug 2021

Sponsor / Collaborator

Shenzhen Salubris Pharmaceuticals Co., Ltd.

100 Clinical Results associated with Enarodustat

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100 Translational Medicine associated with Enarodustat

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100 Patents (Medical) associated with Enarodustat

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40

Literatures (Medical) associated with Enarodustat

01 Nov 2024·Clinical and Experimental Nephrology

The comparison of four hypoxia-inducible factor prolyl hydroxylase inhibitors on drug potency and cost for treatment in patients with renal anemia

Article

Author: Imai, Atsuhiro ; Imai, Enyu

BACKGROUNDFive hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have been approved for marketing in Japan. However, marked differences exist in terms of drug potency, dose requirement, and pharmacokinetics.METHODSThe primary evaluation in this study was the changes in hemoglobin levels, dose escalation, drug potency, and cost among HIF-PHIs, 3 months after the initiation of treatment.RESULTSAll patients treated with HIF-PHI between August 2020 and December 2023 were enrolled in this study. In total, 124 patients were administered daprodustat (N = 37), enarodustat (N = 44), molidustat (N = 13), or vadadustat (N = 30). The mean hemoglobin levels of daprodustat, enarodustat, molidustat, and vadadustat at 3 months were 11.7 g/dL, 11.8 g/dL, 12.2 g/dL, and 11.3 g/dL, respectively. At 3 months, the mean doses of daprodustat, enarodustat, molidustat, and vadadustat increased by 110%, 177%, 125%, and 152%, respectively, from the initial dose. The HIF-PHI potency indices (HPI) of daprodustat, enarodustat, molidustat, and vadadustat at 3 months were 0.168, 0.307, 0.184, and 0.254, respectively. At 3 months, the mean daily costs of daprodustat, enarodustat, molidustat, and vadadustat were JPY 345, JPY 434, JPY 206, and JPY 565, respectively.CONCLUSIONThe difference in dose escalation for anemia treatment among HIF-PHIs is due to differences in drug potency, where the HPI significantly differs among HIF-PHIs. The disparity between the HPI and the cost of the initial dose accounts for the variance in the daily costs of renal anemia treatment among HIF-PHIs.

01 Jun 2024·Life Sciences

The drug-specific properties of hypoxia-inducible factor-prolyl hydroxylase inhibitors in mice reveal a significant contribution of the kidney compared to the liver to erythropoietin induction

Article

Author: Suzuki, Norio ; Saigusa, Daisuke ; Nakai, Taku ; Yamamoto, Masayuki ; Kato, Koichiro ; Fukuuchi, Tomoko ; Koshiba, Seizo

AIMSKidney disease often leads to anemia due to a defect in the renal production of the erythroid growth factor erythropoietin (EPO), which is produced under the positive regulation of hypoxia-inducible transcription factors (HIFs). Chemical compounds that inhibit HIF-prolyl hydroxylases (HIF-PHs), which suppress HIFs, have been developed to reactivate renal EPO production in renal anemia patients. Currently, multiple HIF-PH inhibitors, in addition to conventional recombinant EPO reagents, are used for renal anemia treatment. This study aimed to elucidate the therapeutic mechanisms and drug-specific properties of HIF-PH inhibitors.METHODS AND KEY FINDINGSGene expression analyses and mass spectrometry revealed that HIF-PH inhibitors (daprodustat, enarodustat, molidustat, and vadadustat) alter Epo gene expression levels in the kidney and liver in a drug-specific manner, with different pharmacokinetics in the plasma and urine after oral administration to mice. The drug specificity revealed the dominant contribution of EPO induction in the kidneys rather than in the liver to plasma EPO levels after HIF-PH inhibitor administration. We also found that several HIF-PH inhibitors directly induce duodenal gene expression related to iron intake, while these drugs indirectly suppress hepatic hepcidin expression to mobilize stored iron for hemoglobin synthesis through induction of the EPO-erythroferrone axis.SIGNIFICANCERenal EPO induction is the major target of HIF-PH inhibitors for their therapeutic effects on erythropoiesis. Additionally, the drug-specific properties of HIF-PH inhibitors in EPO induction and iron metabolism have been shown in mice, providing useful information for selecting the proper HIF-PH inhibitor for each renal anemia patient.

01 May 2024·Drug Metabolism and Disposition

Low Molecular Weight Acids and Organic Anion Transporting Polypeptide (OATP1B)-Mediated Hepatic Clearance: In Vitro and In Vivo Evaluation Using Novel Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors (Dustats)

Article

Author: Bi, Yi-An ; Tess, David A ; West, Mark A ; Mathialagan, Sumathy ; Varma, Manthena V S ; Yamaguchi, Emi ; Jordan, Samantha ; Ryu, Sangwoo ; King-Ahmad, Amanda

Organic anion transporting polypeptide (OATP1B) plays a key role in the hepatic clearance of a majority of high molecular weight (MW) acids and zwitterions. Here, we evaluated the role of OATP1B-mediated uptake in the clearance of novel hypoxia-inducible factor prolyl hydroxylase inhibitors ("Dustats"), which are typically low MW (300-400 daltons) aliphatic carboxylic acids. Five acid dustats, namely daprodustat, desidustat, enarodustat, roxadustat and vadadustat, showed specific transport by OATP1B1/1B3 in transporter-transfected HEK293 cells. Neutral compound, molidustat, was not a substrate to OATP1B1/1B3. None of the dustats showed transport by other hepatic uptake transporters, including NTCP, OAT2 and OAT7. In the primary human hepatocytes, uptake of all acids was significantly reduced by rifampin (OATP1B inhibitor); with an estimated fraction transported by OATP1B (f_t _,OATP1B) of up to >80% (daprodustat). Molidustat uptake was minimally inhibited by rifampin; and low permeability acids (desidustat and enarodustat) also showed biliary efflux in sandwich culture human hepatocytes. In vivo, intravenous pharmacokinetics of all 5 acids was significantly altered by a single-dose rifampin (30 mg/kg) in Cynomolgus monkey. Hepatic clearance (non-renal) was about 4-fold (vadadustat) to >11-fod (daprodustat and roxadustat) higher in control group compared to rifampin-treated subjects. In vivo f_t _,OATP1B was estimated to be ~70-90%. In the case of molidustat, rifampin had a minimal effect on overall clearance. Rifampin also considerably reduced volume of distribution of daprodustat and roxadustat. Overall, OATP1B significantly contribute to the hepatic clearance and pharmacokinetics of several dustats, which are low MW carboxylic acids. OATP1B activity should therefore by evaluated in this property space. Significance Statement Our in vitro and in vivo results suggest that OATP1B-mediated hepatic uptake play a significant role in the pharmacokinetics of low MW acidic dustats, which are being developed or approved for the treatment of anemia in chronic kidney disease. Significant active uptake mechanisms are not apparent for the neutral compound, molidustat. Characterization of uptake mechanisms is therefore important in predicting human pharmacokinetics and evaluating drug-drug interactions for low MW acids.

100 Deals associated with Enarodustat

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External Link

KEGG	Wiki	ATC	Drug Bank
D11523	Enarodustat	B03A	DB14985

R&D Status

Approved

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Indication	Country/Location	Organization	Date
chronic renal failure anemia	KR	JW PHARMACEUTICAL Corp.	17 Nov 2022
Anemia of renal disease	JP	Japan Tobacco, Inc.	25 Sep 2020

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
chronic renal failure anemia	Phase 3	CN	Shenzhen Salubris Pharmaceuticals Co., Ltd.	09 Dec 2020
Anemia in chronic kidney disease	Phase 3	CN	Shenzhen Salubris Pharmaceuticals Co., Ltd.	08 Dec 2020
Kidney Failure, Chronic	Phase 3	US	Akros Pharma, Inc.	01 May 2013

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASN2018	Phase 3	Anemia \| Chronic Kidney Diseases Maintenance	-	Enarodustat 2 mg	sbunncjiqh(zbalzbgvfr) = akzjknezhg vtplxgduhu (nixjgchbok )	Positive	23 Oct 2018
				Enarodustat 4 mg	sbunncjiqh(zbalzbgvfr) = caaehfyjul vtplxgduhu (nixjgchbok )
FO019 (ERA2015)	Not Applicable	Anemia \| Anemia in chronic kidney disease \| Chronic Kidney Diseases Maintenance hemoglobin \| Erythropoiesis Stimulating Agents (ESAs) \| iv iron ... View more	40	JTZ-951 1 mg	(mxwjrgowec) = The results of reticulocyte count, hematocrit level and red blood cells in terms of changes from baseline at week 8 were similar to that in hemoglobin rvzvdirelp (kxcuxvylnq ) View more	Positive	21 May 2015
				JTZ-951 3 mg
FP380 (ERA2015)	Not Applicable	Anemia in chronic kidney disease hemoglobin \| erythropoietin	22	JTZ-951 1 mg	(cimprxrgju) = The results of reticulocyte count, hematocrit level and red blood cells in terms of changes from baseline at Week 6 were similar to that in hemoglobin dwgjtykhde (mlpkgqttwt ) View more	Positive	21 May 2015