Enfuvirtide

Enfuvirtide

Clinical data
Pregnancy category	B2 (Au), B (U.S.)
Routes of administration	Subcutaneous (SC)
ATC code	J05AX07 (WHO)
Legal status
Legal status	S4 (Au), POM (UK), ℞-only (U.S.)
Pharmacokinetic data
Bioavailability	84.3% (SC)
Protein binding	92%
Metabolism	Hepatic
Elimination half-life	3.8 hours
Excretion	unknown
Identifiers
IUPAC name Acetyl-YTSLIHSLIEESQNQ QEKNEQELLELDKWASLWNWF-amide
CAS Number	159519-65-0
PubChem CID	16130199
DrugBank	BTD00106
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C202H298N50O64
Molar mass	4492.1 g/mol

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Overview

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.

Structural 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 host cell receptor CD4+ by the protein GP120; upon binding, GP120 deforms allowing the viral protein GP41 to embed itself into the host cell's plasma membrane, entry inhibitors bind to GP41 preventing the creation of an entry pore for the capsid of the virus keeping it out of the cell. [1]

Microbiology

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

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.

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.

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.