- Enfuvirtide
drugbox
IUPAC_name = Acetyl-YTSLIHSLIEESQNQ QEKNEQELLELDKWASLWNWF-amide
width = 280
CAS_number = 159519-65-0
ATC_prefix = J05
ATC_suffix = AX07
ATC_supplemental =
PubChem = 16130199
DrugBank = BTD00106
C=202 | H=298 | N=50 | O=64
molecular_weight = 4492.1 g/mol
bioavailability = 84.3% (SC)
protein_bound = 92%
metabolism = Hepatic
elimination_half-life = 3.8 hours
excretion = unknown
pregnancy_category = B2 (Au), B (U.S.)
legal_status = S4 (Au), POM (UK), ℞-only (U.S.)
routes_of_administration =Subcutaneous (SC)Enfuvirtide (INN) is an
HIV fusion inhibitor , the first of a novel class ofantiretroviral drug s used incombination therapy for the treatment ofHIV -1 infection. It is marketed under the trade name Fuzeon (Roche).Enfuvirtide therapy costs an estimated USD$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.
tructural formula
Ac-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-NH2History
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 withHoffmann-La Roche to complete the development of the drug. It was approved by the U.S.Food and Drug Administration (FDA) onMarch 13 ,2003 as the first HIVfusion inhibitor , a new class of antiretroviral drugs. It was approved on the basis of two studies (TORO 1 and TORO 2) which compared the effect of optimized regimens of antiretroviral medication with and without the addition of enfuvirtide on serumviral load .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. Abiomimetic peptide , enfuvirtide was rationally designed to mimic components of theHIV -1 fusion machinery and displace them, preventing normal fusion. Drugs that disrupt fusion ofvirus and target cell are termedentry inhibitors orfusion inhibitor s.HIV binds to the host CD4+ cell receptor via the viral protein GP120; upon binding, GP120 deforms allowing the viral protein GP41 to embed itself into the host cell's plasma membrane. Enfuvirtide binds to GP41 preventing the creation of an entry pore for the capsid of the virus, keeping it out of the cell. [Lalezari JP, Eron JJ, Carlson M, et al. A phase II clinical study of the long-term safety and antiviral activity of enfuvirtide-based antiretroviral therapy. AIDS 2003;17:691—8.]
Microbiology
Enfuvirtide is considered to be active against HIV-1 only. Low activity against HIV-2 isolates has been demonstrated "
in vitro ".Roche Products Pty Ltd. Fuzeon (Australian Approved Product Information). Dee Why (NSW): Roche; 2005.]Variable susceptibility to enfuvirtide has been observed in clinical isolates, with
acquired resistance the result of a mutated 10amino acid motif in viral gp41.Primary resistance , however, has yet to be observed.Greenberg ML, Cammack N. Resistance to enfuvirtide, the first HIV fusion inhibitor. J Antimicrob Chemother 2004;54(2):333-40. PMID 15231762]Clinical use
Indications
Enfuvirtide is indicated for the treatment of HIV-1 infection, in
combination therapy with other antiretrovirals, in patients where all other treatments have failed.Rossi S, editor.Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3]Dosage forms
By virtue of its peptide nature, enfuvirtide is marketed in injectable form. The lyophilised enfuvirtide powder must be reconstituted by the patient and administered twice daily by
subcutaneous injection.Adverse effects
Common
adverse drug reaction s (≥1% of patients) associated with enfuvirtide therapy include: injection site reactions (pain, hardening of skin,erythema ,nodule s,cyst s, itch; experienced by nearly all patients, particularly in the first week),peripheral neuropathy ,insomnia , depression, cough,dyspnoea , anorexia,arthralgia , infections (including bacterialpneumonia ) and/oreosinophilia . Varioushypersensitivity reactions occur infrequently (0.1–1% of patients), symptoms of which include rash, fever, nausea, vomiting, chills, rigors,hypotension , elevated hepatictransaminase s; and possibly more severe reactions includingrespiratory distress ,glomerulonephritis and/oranaphylaxis – rechallenge is not recommended.References
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