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 of antiretroviral drugs used in combination therapy for the treatment of HIV-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-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 as the first HIV fusion 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 serum viral 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. A biomimetic peptide, enfuvirtide was rationally 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.

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 10 amino 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 reactions (≥1% of patients) 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 hepatic transaminases; and possibly more severe reactions including respiratory distress, glomerulonephritis and/or anaphylaxis – rechallenge is not recommended.

References