Bulevirtide (Myrcludex B; MyrB)   中文名称: 布尔韦肽

Absorption, Distribution and Excretion
Human pharmacokinetic data for bulevirtide is limited in the literature. In rats, bulevirtide administered by subcutaneous injection is rapidly absorbed with a Cmax of 4 to 6 hours. The estimated bioavailability is 85% in humans, and steady-state concentrations are expected to occur within weeks of initiating treatment. The AUC for bulevirtide after a 2mg subcutaneous dose was found to be approximately 46 ng/ml.h with a Tmax of 0.5 hours.
Elimination through target (NTCP) binding is expected to be the main route of elimination for bulevirtide. In healthy volunteers, bulevirtide was not found to be excreted in the urine.
The volume of distribution of bulevirtide is estimated to be lower than total body water. In animals, bulevirtide distributes into the liver, gastrointestinal tract, kidney, and bladder.
The clearance after of bulevirtide after subcutaneous administration (CL/F) in healthy volunteers ranged from 7.98 L/h (±2.02) to 62 L/h (±16.7), depending on the dose administered. The clearance of bulevirtide decreases as the dose increases.

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Metabolism / Metabolites
To date, metabolism studies have not been conducted on bulevirtide. It is expected to be catabolized by peptidases to smaller peptides and amino acids, with no active metabolites.

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Biological Half-Life
The half-life of bulevirtide ranges between 4 and 7 hours in healthy adults.

Protein Binding
The plasma protein binding of bulevirtide is >99%, and it is primarily bound to albumin.

[1]. Bulevirtide for treatment of patients with HDV infection and compensated cirrhosis: A (huge) step in the right direction. Liver Int. 2021 Jul;41(7):1441-1442.

[2]. Clinical effects of NTCP-inhibitor myrcludex B. J Viral Hepat. 2021 Jun;28(6):852-858.

[3]. Drugs Today (Barc). 2021 Jul;57(7):433-448. doi: 10.1358/dot.2021.57.7.3283861.

Hepatitis D is considered the most severe type of viral hepatitis and leads to the rapid development of cirrhosis, severe decompensation of liver function, and an increased risk of mortality. Until recently, there have been extremely limited treatments available for Hepatitis D infection. Bulevirtide, also known as Hepcludex, is a first-in-class entry inhibitor for the treatment of chronic Hepatitis D infection developed by MYR Pharmaceuticals, now part of Gilead. It was first approved for use in the EU on May 28, 2020; bulevirtide has been granted PRIME scheme eligibility and Orphan Drug Designation by the European Medicines Agency. In the USA, bulevirtide has been granted Orphan Drug Designation and Breakthrough Therapy Designation. Due to potentially beneficial synergistic effects in treating chronic Hepatitis D, bulevirtide is also under investigation in clinical trial NCT03852433 (Phase 2b Study of Bulevirtide With [Peginterferon Alfa-2a]) in Patients With CHD. Completion of this clinical trial is anticipated in early 2023.

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Drug Indication
Bulevirtide is indicated for the treatment of chronic Hepatitis D infection in HDV-RNA positive adult patients with compensated liver disease.
Hepcludex is indicated for the treatment of chronic hepatitis delta virus (HDV) infection in plasma (or serum) HDV-RNA positive adult patients with compensated liver disease.
Treatment of chronic hepatitis D infection

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Mechanism of Action
The sodium taurocholate co-transporting polypeptide (NTCP) serves to transport bile acids in the sodium salt form to the liver from the portal circulation. It is an important component of enterohepatic circulation. The Hepatitis D virus replicates independently within liver cells but requires the hepatitis B surface antigen in order to propagate. Hepatitis B and D viruses enter hepatocytes through the binding of NTCP (sodium/taurocholate cotransporting polypeptide) to the Hepatitis B virus preS1 surface protein domain. Bulevirtide binds and subsequently inactivates the hepatitis B (HBV) and HDV receptors on hepatocytes. Bulevirtide blocks the NTCP binding site, subsequently blocking the entry of the viruses into cells. This prevents viral entry and replication, reducing symptoms of Hepatitis D infection.

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Pharmacodynamics
Bulevirtide prevents Hepatitis D entry into cells. It is effective in the reduction of Hepatitis D virus (HDV) RNA levels and improvement of liver inflammation in cases of Hepatitis D infection.

C234H329N65O71

5398.86

5397.618

2012558-47-1

134687648

White to off-white solid powder

-16.7

2160

65

76

166

385

14300

44

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WQNDXLHKAMIGEX-WOAPPVHJSA-N

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(4S)-4-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-4-amino-2-[[(2S)-1-[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-4-amino-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-1-[(2S)-4-amino-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S,3R)-3-hydroxy-2-[[2-(tetradecanoylamino)acetyl]amino]butanoyl]amino]-4-oxobutanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-3-methylbutanoyl]pyrrolidine-2-carbonyl]amino]-4-oxobutanoyl]pyrrolidine-2-carbonyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-3-phenylpropanoyl]pyrrolidine-2-carbonyl]amino]-3-carboxypropanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]-3-carboxypropanoyl]pyrrolidine-2-carbonyl]amino]propanoyl]amino]-3-phenylpropanoyl]amino]acetyl]amino]propanoyl]amino]-4-oxobutanoyl]amino]-3-hydroxypropanoyl]amino]-4-oxobutanoyl]amino]-4-oxobutanoyl]pyrrolidine-2-carbonyl]amino]-3-carboxypropanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-carboxypropanoyl]amino]-3-phenylpropanoyl]amino]-4-oxobutanoyl]pyrrolidine-2-carbonyl]amino]-4-oxobutanoyl]amino]hexanoyl]amino]-3-carboxypropanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]pyrrolidine-2-carbonyl]amino]-5-[[(2S)-1-[[(2S)-4-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[(2-amino-2-oxoethyl)amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-oxopentanoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮和光照。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~9.26 mM)

配方 1 中的溶解度: 2.5 mg/mL (0.46 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 悬浮液；超声助溶。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (0.46 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。