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Bulevirtide (Myrcludex B; MyrB; Hepcludex) is a first-in-class entry inhibitor approved as an antiviral medication for the treatment of chronic hepatitis D. As a novel virion entry inhibitor, Bulevirtide blocks the virion's hepatocyte pathway of entry, the hepatic sodium/taurocholate cotransporting polypeptide (NTCP) receptor. In July 2020 bulevirtide was authorized for use in the E.U. following a positive opinion by the European Medicines Agency (EMA) for the treatment of chronic HDV infection in HDV RNA-positive adult patients with compensated liver disease.
| ADME/Pharmacokinetics |
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. 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. Biological Half-Life The half-life of bulevirtide ranges between 4 and 7 hours in healthy adults. |
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| Toxicity/Toxicokinetics |
Protein Binding
The plasma protein binding of bulevirtide is >99%, and it is primarily bound to albumin. |
| References | |
| Additional Infomation |
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.
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 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. 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. |
| Molecular Formula |
C234H329N65O71
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|---|---|
| Molecular Weight |
5398.86
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| Exact Mass |
5397.618
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| CAS # |
2012558-47-1
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| PubChem CID |
134687648
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| Appearance |
White to off-white solid powder
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| LogP |
-16.7
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| Hydrogen Bond Donor Count |
65
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| Hydrogen Bond Acceptor Count |
76
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| Rotatable Bond Count |
166
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| Heavy Atom Count |
385
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| Complexity |
14300
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| Defined Atom Stereocenter Count |
44
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| SMILES |
CCCCCCCCCCCCCC(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)N)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CC3=CC=CC=C3)C(=O)N[C@@H](CC4=CC=CC=C4)C(=O)N5CCC[C@H]5C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC6=CNC=N6)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N7CCC[C@H]7C(=O)N[C@@H](C)C(=O)N[C@@H](CC8=CC=CC=C8)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)N9CCC[C@H]9C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(=O)N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N
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| InChi Key |
WQNDXLHKAMIGEX-WOAPPVHJSA-N
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| InChi Code |
InChI=1S/C248H355N65O72/c1-16-17-18-19-20-21-22-23-24-25-38-75-193(327)265-118-196(330)304-205(133(15)316)241(378)295-163(104-188(256)322)224(361)283-152(91-127(6)7)216(353)303-175(122-315)232(369)306-204(129(10)11)248(385)313-88-53-74-182(313)239(376)301-172(107-191(259)325)246(383)312-87-50-70-178(312)235(372)291-150(89-125(2)3)209(346)268-120-195(329)274-154(93-135-56-32-27-33-57-135)217(354)296-168(95-137-60-36-29-37-61-137)242(379)308-83-49-72-180(308)237(374)294-167(111-201(339)340)230(367)286-157(98-140-115-261-123-269-140)220(357)277-148(76-78-183(251)317)213(350)282-151(90-126(4)5)215(352)300-173(112-202(341)342)247(384)307-82-47-68-176(307)233(370)273-132(14)208(345)279-153(92-134-54-30-26-31-55-134)210(347)267-119-194(328)271-130(12)206(343)280-160(101-185(253)319)226(363)302-174(121-314)231(368)288-161(102-186(254)320)225(362)299-171(106-190(258)324)245(382)311-86-52-73-181(311)238(375)293-166(110-200(337)338)229(366)285-156(96-138-113-263-144-64-41-39-62-142(138)144)219(356)290-165(109-199(335)336)227(364)284-155(94-136-58-34-28-35-59-136)218(355)298-170(105-189(257)323)244(381)310-85-51-71-179(310)236(373)292-162(103-187(255)321)223(360)275-146(66-43-45-80-249)212(349)289-164(108-198(333)334)228(365)287-158(99-141-116-262-124-270-141)221(358)297-169(97-139-114-264-145-65-42-40-63-143(139)145)243(380)309-84-48-69-177(309)234(371)278-149(77-79-197(331)332)211(348)272-131(13)207(344)281-159(100-184(252)318)222(359)276-147(67-44-46-81-250)214(351)305-203(128(8)9)240(377)266-117-192(260)326/h26-37,39-42,54-65,113-116,123-133,146-182,203-205,263-264,314-316H,16-25,38,43-53,66-112,117-122,249-250H2,1-15H3,(H2,251,317)(H2,252,318)(H2,253,319)(H2,254,320)(H2,255,321)(H2,256,322)(H2,257,323)(H2,258,324)(H2,259,325)(H2,260,326)(H,261,269)(H,262,270)(H,265,327)(H,266,377)(H,267,347)(H,268,346)(H,271,328)(H,272,348)(H,273,370)(H,274,329)(H,275,360)(H,276,359)(H,277,357)(H,278,371)(H,279,345)(H,280,343)(H,281,344)(H,282,350)(H,283,361)(H,284,364)(H,285,366)(H,286,367)(H,287,365)(H,288,368)(H,289,349)(H,290,356)(H,291,372)(H,292,373)(H,293,375)(H,294,374)(H,295,378)(H,296,354)(H,297,358)(H,298,355)(H,299,362)(H,300,352)(H,301,376)(H,302,363)(H,303,353)(H,304,330)(H,305,351)(H,306,369)(H,331,332)(H,333,334)(H,335,336)(H,337,338)(H,339,340)(H,341,342)/t130-,131-,132-,133+,146-,147-,148-,149-,150-,151-,152-,153-,154-,155-,156-,157-,158-,159-,160-,161-,162-,163-,164-,165-,166-,167-,168-,169-,170-,171-,172-,173-,174-,175-,176-,177-,178-,179-,180-,181-,182-,203-,204-,205-/m0/s1
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| Chemical Name |
(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
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~50 mg/mL (~9.26 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (0.46 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (0.46 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.1852 mL | 0.9261 mL | 1.8522 mL | |
| 5 mM | 0.0370 mL | 0.1852 mL | 0.3704 mL | |
| 10 mM | 0.0185 mL | 0.0926 mL | 0.1852 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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