Enfuvirtide

From WikiProjectMed
Jump to navigation Jump to search
Enfuvirtide
Enfuvirtid.svg
Names
Trade namesFuzeon
Clinical data
Drug classHIV fusion inhibitor[1]
Main usesTreat and prevent HIV/AIDS[1]
Side effectsPain at site of injection, peripheral nerve damage, weight loss[2]
Pregnancy
category
  • AU: B2
  • US: B (No risk in non-human studies)
Routes of
use
Subcutaneous (SC)
Typical dose90 mg BID[2]
External links
AHFS/Drugs.comMonograph
US NLMEnfuvirtide
MedlinePlusa603023
Legal
License data
Legal status
Pharmacokinetics
Bioavailability84.3% (SC)
Protein binding92%
MetabolismLiver
Elimination half-life3.8 hours
Excretionunknown
Chemical and physical data
FormulaC204H301N51O64
Molar mass4491.945 g·mol−1
3D model (JSmol)
  • CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](Cc1c[nH]c2c1cccc2)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc3c[nH]c4c3cccc4)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](Cc5c[nH]c6c5cccc6)C(=O)N[C@@H](Cc7ccccc7)C(=O)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](Cc8cnc[nH]8)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](Cc9ccc(cc9)O)NC(=O)C
  • InChI=1S/C204H301N51O64/c1-20-102(15)166(253-195(310)137(75-100(11)12)239-200(315)150(93-258)251-190(305)143(82-112-90-215-95-219-112)248-203(318)167(103(16)21-2)254-196(311)138(76-101(13)14)240-201(316)151(94-259)252-204(319)168(105(18)260)255-197(312)139(221-106(19)261)78-108-45-47-113(262)48-46-108)202(317)233-131(58-68-164(280)281)178(293)228-130(57-67-163(278)279)182(297)250-149(92-257)198(313)232-125(52-62-155(210)266)179(294)245-145(84-157(212)268)191(306)229-124(51-61-154(209)265)175(290)224-122(49-59-152(207)263)173(288)226-126(53-63-159(270)271)176(291)222-120(43-31-33-69-205)172(287)244-144(83-156(211)267)192(307)231-127(54-64-160(272)273)177(292)225-123(50-60-153(208)264)174(289)227-128(55-65-161(274)275)180(295)235-134(72-97(5)6)185(300)237-133(71-96(3)4)184(299)230-129(56-66-162(276)277)181(296)236-135(73-98(7)8)187(302)247-147(86-165(282)283)194(309)223-121(44-32-34-70-206)171(286)241-140(79-109-87-216-117-40-28-25-37-114(109)117)183(298)220-104(17)170(285)249-148(91-256)199(314)238-136(74-99(9)10)186(301)242-142(81-111-89-218-119-42-30-27-39-116(111)119)189(304)246-146(85-158(213)269)193(308)243-141(80-110-88-217-118-41-29-26-38-115(110)118)188(303)234-132(169(214)284)77-107-35-23-22-24-36-107/h22-30,35-42,45-48,87-90,95-105,120-151,166-168,216-218,256-260,262H,20-21,31-34,43-44,49-86,91-94,205-206H2,1-19H3,(H2,207,263)(H2,208,264)(H2,209,265)(H2,210,266)(H2,211,267)(H2,212,268)(H2,213,269)(H2,214,284)(H,215,219)(H,220,298)(H,221,261)(H,222,291)(H,223,309)(H,224,290)(H,225,292)(H,226,288)(H,227,289)(H,228,293)(H,229,306)(H,230,299)(H,231,307)(H,232,313)(H,233,317)(H,234,303)(H,235,295)(H,236,296)(H,237,300)(H,238,314)(H,239,315)(H,240,316)(H,241,286)(H,242,301)(H,243,308)(H,244,287)(H,245,294)(H,246,304)(H,247,302)(H,248,318)(H,249,285)(H,250,297)(H,251,305)(H,252,319)(H,253,310)(H,254,311)(H,255,312)(H,270,271)(H,272,273)(H,274,275)(H,276,277)(H,278,279)(H,280,281)(H,282,283)/t102-,103-,104-,105+,120-,121-,122-,123-,124-,125-,126-,127-,128-,129-,130-,131-,132-,133-,134-,135-,136-,137-,138-,139-,140-,141-,142-,143-,144-,145-,146-,147-,148-,149-,150-,151-,166-,167-,168-/m0/s1 checkY
  • Key:PEASPLKKXBYDKL-FXEVSJAOSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Enfuvirtide, sold under the brand name Fuzeon, is a medication used to treat and prevent HIV/AIDS.[1] It is used together with other medications when resistance has occurred.[2] It is given by injection under the skin.[1]

Common side effects include pain at the site of injection, peripheral nerve damage, and weight loss.[2] Other side effects may include osteonecrosis, liver problems, allergic reactions, and immune reactivation syndrome.[2][3] While there is no evidence of harm in pregnancy, such use has not been well studied.[4] It is an HIV fusion inhibitor.[1]

Enfuvirtide was approved for medical use in the United States and Europe in 2003.[1][2] In the United Kingdom it costs the NHS about £1,100 a month as of 2021.[5] This amount in the United States costs about 3,500 USD.[6]

Medical use

Enfuvirtide is indicated for the treatment of HIV-1 infection, in combination therapy with other antiretrovirals, in people where all other treatments have failed.[7]

Dosage

The typical dose is 90 mg twice per day.[2] In children a dose of 2 mg/kg may be used.[3]

By virtue of its peptide nature, enfuvirtide is marketed in injectable form. The lyophilised enfuvirtide powder must be reconstituted and administered twice daily by subcutaneous injection. Due to the chronic nature of this kind of therapy, this dosage form may be a major problem for adherence to this drug.[8]

Side effects

Common side effects (≥1% of people) associated with enfuvirtide therapy include: injection site reactions (pain, hardening of skin, erythema, nodules, cysts, itch; experienced by nearly all patients, particularly in the first week), peripheral neuropathy, insomnia, depression, cough, dyspnoea, anorexia, arthralgia, infections (including bacterial pneumonia) and/or eosinophilia. Various hypersensitivity reactions occur infrequently (0.1–1% of patients), symptoms of which include rash, fever, nausea, vomiting, chills, rigors, hypotension, elevated liver transaminases; and possibly more severe reactions including respiratory distress, glomerulonephritis and/or anaphylaxisrechallenge is not recommended.[7]

Pharmacology

Mechanism of action

Enfuvirtide works by disrupting the HIV-1 molecular machinery at the final stage of fusion with the target cell, preventing uninfected cells from becoming infected. A biomimetic peptide, enfuvirtide was designed to mimic components of the HIV-1 fusion machinery and displace them, preventing normal fusion. Drugs that disrupt fusion of virus and target cell are termed entry inhibitors or fusion inhibitors.[citation needed]

HIV binds to the host CD4+ cell receptor via the viral protein gp120; gp41, a viral transmembrane protein, then undergoes a conformational change that assists in the fusion of the viral membrane to the host cell membrane. Enfuvirtide binds to gp41 preventing the creation of an entry pore for the capsid of the virus, keeping it out of the cell.[9]

Enfuvirtide is also an activator of the chemotactic factor receptor, formyl peptide receptor 1, and thereby activates phagocytes and presumably other cells bearing this receptor (see formyl peptide receptors).[10] The physiological significance of this activation is unknown.

Microbiology

Enfuvirtide is considered to be active against HIV-1 only. Low activity against HIV-2 isolates has been demonstrated in vitro.[11]

Variable susceptibility to enfuvirtide has been observed in clinical isolates, with acquired resistance the result of a mutated 10 amino acid motif in viral gp41. Primary resistance, however, has yet to be observed.[12]

Chemistry

Enfuvirtid.svg

Enfuvirtide is a 36-amino acid peptide with the following sequence:[citation needed]

CH3CO-Tyr-Thr-Ser-Leu-Ile-His-Ser-Leu-Ile-Glu-Glu-Ser-Gln-Asn-Gln-Gln-Glu-Lys-Asn-Glu-Gln-Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-Ser-Leu-Trp-Asn-Trp-Phe-NH2

History

Enfuvirtide originated at Duke University, where researchers formed a pharmaceutical company known as Trimeris. Trimeris began development on enfuvirtide in 1996 and initially designated it "T-20". In 1999, Trimeris entered into partnership with Hoffmann-La Roche to complete the development of the drug. It was approved by the U.S. Food and Drug Administration (FDA) on March 13, 2003[13] as the first HIV fusion inhibitor, a new class of antiretroviral drugs. It was approved on the basis of two studies which compared the effect of optimized regimens of antiretroviral medication with and without the addition of enfuvirtide on serum viral load.[citation needed]

Society and culture

Economics

Enfuvirtide therapy costs an estimated US$25,000 per year in the United States. Its cost and inconvenient dosing regimen are factors behind its use as a reserve, for salvage therapy in patients with multi-drug resistant HIV.

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 "Enfuvirtide Monograph for Professionals". Drugs.com. Retrieved 15 December 2021.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "Fuzeon". Retrieved 15 December 2021.
  3. 3.0 3.1 "DailyMed - FUZEON- enfuvirtide kit". dailymed.nlm.nih.gov. Retrieved 15 December 2021.
  4. "Enfuvirtide (Fuzeon) Use During Pregnancy". Drugs.com. Retrieved 15 December 2021.
  5. BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 680. ISBN 978-0857114105.
  6. "Enfuvirtide Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 15 December 2021.
  7. 7.0 7.1 Rossi S, ed. (2006). Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd. ISBN 0-9757919-2-3.
  8. Klein R (13 March 2003). "FDA approves Fuzeon". fda.gov. Archived from the original on 25 August 2009. Retrieved 2 July 2011.
  9. Lalezari JP, Eron JJ, Carlson M, Cohen C, DeJesus E, Arduino RC, et al. (March 2003). "A phase II clinical study of the long-term safety and antiviral activity of enfuvirtide-based antiretroviral therapy". AIDS. 17 (5): 691–8. doi:10.1097/00002030-200303280-00007. PMID 12646792. S2CID 32014873.
  10. Su SB, Gong WH, Gao JL, Shen WP, Grimm MC, Deng X, et al. (June 1999). "T20/DP178, an ectodomain peptide of human immunodeficiency virus type 1 gp41, is an activator of human phagocyte N-formyl peptide receptor". Blood. 93 (11): 3885–92. doi:10.1182/blood.V93.11.3885. PMID 10339497.
  11. Roche Products Pty Ltd. Fuzeon (Australian Approved Product Information). Dee Why (NSW): Roche; 2005.
  12. Greenberg ML, Cammack N (August 2004). "Resistance to enfuvirtide, the first HIV fusion inhibitor". The Journal of Antimicrobial Chemotherapy. 54 (2): 333–40. doi:10.1093/jac/dkh330. PMID 15231762.
  13. "Drugs@FDA: FDA Approved Drug Products – Fuzeon (Click on 'Approval Date(s) and History, Letters, Labels, Reviews for NDA 021481')". accessdata.fda.gov. United States Food and Drug Administration. Retrieved 6 January 2019.

External links

External sites:
Identifiers: