In: Drug11 Jun 2010
Clinical studies involving enfuvirtide are limited. No clinically significant drug interaction was reported when this medication was used in combination with the other antiretroviral drugs. In cell culture media assays, enfuvirtide exhibited additive-to-synergistic effects when it was combined with individual members of various antiretroviral agents, such as zidovudine (AZT, Glaxo-SmithKline), (3TC, GlaxoSmithKline), nelfinavir (NFV, Agouron), (IDV, Merck), and generic efavirenz (EFV, Sustiva canadian, Bristol-Myers Squibb Virol-ogy). A human microsomal study in vitro suggests that enfuvirtide is neither an inducer nor an inhibitor of cyto-chrome P-450 (CYP-450) enzymes or its substrates.
The HIV Netherlands, Australia, Thailand Research Collaboration (HIVNAT) Study Group conducted three pharmaco-kinetic interaction trials. In each study, 12 patients infected with HIV-1 received one of the following regimens with enfu-virtide: 1,000 mg of saquanivir (Forto-vase®, Roche) twice daily, boosted with 100 mg of ritonavir (Abbott), 200 mg of ritonavir twice daily, or 600 mg of rifampin (e.g., Rifadin®, Aventis) once daily. Boyd and colleagues reported a low potential for drug-drug interactions that were consistent with the expectations of a peptide drug such as enfuvirtide.
HIV-1 resistance to enfuvirtide was assessed in TORO-1 and TORO-2. In both trials, the researchers studied samples from baseline values and at treatment failure. Currently, no standard assays are available for fusion inhibitors. Consequently, the investigators used a susceptibility test, developed by Viro-Logic, to determine enfuvirtide resistance and sequencing of the gp41 amino acids at positions 36 to 45. They evaluated the ability of this susceptibility assay to determine which patients had baseline resistance that might predict subsequent drug failure and assessed the differences between susceptibility to enfuvirtide at baseline and after treatment failure.
Greenberg et al. studied genotypic resistance in the patients who did not respond to therapy and noted a large number of mutations in the gp41 amino acids 36-45.14 Mutations at positions 36, 38, and 43 are common and tend to produce reduced susceptibility. Mutations at these positions were found either alone or in combination and resulted in varying degrees of enfuvirtide-reduced susceptibility.
Kilby et al. also studied the pharmaco-kinetics, safety, and resistance parameters of enfuvirtide. In a randomized group of six, 78 patients received 12.5, 25, 50, or 100 mg of subcutaneous enfuvir-tide plus an optimized background regimen. The investigators performed geno-typing between amino acids 1 and 175 of the gp41 protein using a Perkin-Elmer ABI Model Prism™ DNA 377 sequencing system. It was found that the incidence of genotypic or phenotypic resistance in the groups receiving the smaller dose was lower (19%) than in the high-dose groups (50%). Current and previous studies suggest that laboratory susceptibility to enfuvirtide varies among patients; however, the differences in laboratory susceptibility have not translated into clinical failure. canadian pharmacy viagra
Several other agents indicated for use against viral entry, called entry inhibitors, are in various stages of preclinical studies. These agents include the second-generation fusion inhibitor T-1249 as well as some attachment and chemokine co-receptor inhibitors. Preliminary results of an open-label, 10-day dosing trial of T-1249 in patients not responding to an enfuvirtide regimen were presented at the Tenth Conference on Retroviruses and Opportunistic Infections. At day 11, T-1249 exhibited potent but short-term activity in most patients who did not respond to T-20 therapy. Given these favorable outcomes, T-1249 might be an option for patients who do not improve with enfuvirtide therapy.
As a result of two 24-week clinical trials, enfuvirtide is currently indicated for use in combination with other anti-retroviral agents for the treatment of HIV-1 infection in treatment-experienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy.
DOSAGE AND ADMINISTRATION
Enfuvirtide injection is available in the form of single-use vials. Each vial contains 108 mg of enfuvirtide, with 1.1 ml of sterile water needed for reconstitution before administration. The dose for adults is 90 mg subcutaneously twice daily; for pediatric patients six years of age or older, the recommended dose is 2 mg/kg, or a maximum of 90 mg given subcutaneously twice daily. The Pedi-atric AIDS Clinical Trial Group (PACTG) is currently investigating dosing recommendations for children younger than six years of age.
The price of a month’s supply of enfuvirtide is approximately $1,715, with an annual cost of approximately $20,570. The high cost of this medication may discourage some patients from using it and third-party payers from providing coverage. Other antiretroviral agents are less expensive, ranging from less than $300 per month (e.g., didanosine [Videx®, Bristol-Myers Squibb Immunology]) up to $700 or more per month (e.g., ritonavir). Comparative costs of some antiretroviral agents are presented in the August 2003 issue of P&T on page 539.
HIV-1 resistance to the currently available antiretroviral drugs is common. In addition, a high pill burden and deleterious side effects of the current agents are major contributing factors to non-compliance in HIV-infected patients. Consequently, there is a dire need to develop other medications that do not have these shortcomings.
In light of its unique mechanism of action, favorable safety profile, and ease of administration, enfuvirtide may bring a new optimism to the treatment of HIV infection. Enfuvirtide’s accelerated approval was based on results from two major clinical studies sponsored by Roche laboratories, and these studies suggest that this medication offers a therapeutic alternative for resistant HIV-1 infection.
Compared with the other antiretroviral drugs, however, the high cost of enfu-virtide might limit its use to a small group of patients. It is estimated that 50,000 to 100,000 HIV patients are suitable candidates for enfuvirtide therapy.
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