INDICATIONS

• Enfuvirtide in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection in treatment-experienced pts with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

FORMS

*Costs (rounded to the nearest dollar) are based on usual adult dosing per day, are representative of "Average Wholesale Price" (AWP), and are current within the prior three months.

^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

• 90 mg (1 mL) SC q12h into upper arm, anterior thigh or abdomen with each injection given at a site different from the preceding injection site. Do not inject where large nerves course close to skin, over a blood vessel, into moles, scar tissue, tattoos, burn sites, or around the navel.
• Prior to administration, reconstitute with 1.1 mL of sterile water, giving a volume of 1.2 mL.
• Once reconstituted it must be refrigerated and used within 24 hrs.

RENAL DOSING

ADVERSE DRUG REACTIONS

• Local site reaction (grade 3 or 4) including pain (9%), erythema (32%), pruritus (4%), induration (57%), and nodules or cysts (26%), leading to discontinuation in 3%.

• Eosinophilia
• Bacterial pneumonia (4.68 vs. 0.61 events per 100 pts-yr in treatment and control arms, respectively).
• With use of Biojector needle-free device: nerve pain (neuralgia and/or paresthesia) lasting up to 6 months at anatomical sites where large nerves course close to the skin; bruising; hematomas.

DRUG INTERACTIONS

• Not an inhibitor or inducer CYP3A4, CYP2D6, CYP1A2, CYP2C19 or CYP2E1 substrates. As expected, ENF does not interact with SQV, RTV, or rifampin.
• In an observational study, TPV Cmin was increased by approx. 50% with ENF co-administration. Critical factor such as food-effect and adherence were not objectively measured. Limitations of the study design could also have affected results .

RESISTANCE

• No cross-resistance with NRTIs, NNRTIs, or PIs. In vitro, clinical isolates resistant to NRTI, NNRTI, or PIs retained susceptibility to ENF.
• A 21-fold (range, <1- 422-fold) decrease in susceptibility to ENF has been correlated with genotypic changes in gp41 amino acids 36-45 (36, 38, 40, 42, 43, and 45).

PHARMACOLOGY

• Absorption: Well absorbed from SC site with bioavailability of 84.3% (+/- 15.5%).
• Metabolism and Excretion: Undergoes catabolism. Exact pathway of ENF metabolism is unknown. In vitro, undergoes a non-NADPH dependent hydrolysis.
• Protein Binding: 92%
• Cmax, Cmin, and AUC: Following 90 mg SC, mean Cmax was 5.0 +/-1.7 mcg/mL, Cmin was 3.3+/-1.6 mcg/mL, and AUC was 48.7 +/- 19.1 mcg/mL hr. Cmin 2.2 mcg/mL was associated with virologic suppression (Bonora S et al. CROI 2005 abstract 643)
• T1/2: 3.8 +/- 0.6 h
• Distribution: Vd=5.5 +/- 1.1L

COMMENTS

• Pros: Active against PI-, NNRTI-, and NRTI-resistance virus; good response if background regimen includes >2 active ARTs; well studied in ART-experienced pts.
• Cons: SC administration; injection site reactions; time consuming reconstitution process; expensive; requires extensive pt education and training.

References

1. Lazzarin A, Queiroz-Telles F, Frank I, et al. et al. ; TMC 114/r provides durable viral load suppression in treatment-experienced patients: POWER 1 and 2 combined Week 48 analysis. ; Presented at the 16th International AIDS Conference, August 13-18m 2006, Toronto, Canada. ; 2006; Vol.
   Comments:61% of DRV/r-treated pts and 15% of control pts achieved >1 log reduction in VL though wk 48. VL <50 achieved in 46% and 10% of DRV/r and control pts, respectively (p<0.003). Darunavir-treated pts who were naive to ENF had a significantly greater VL if they included ENF in their background regimen. 21/36 achieved a VL reduction of at least 1 log, compared with only 4/35 ENF-naive pts who did not receive DRV/r.
   
   
2. Hicks CB, Cahn P, Cooper DA, et al.; Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials.; Lancet; 2006; Vol. 368; pp. 466-75;
   ISSN: 1474-547X;
   PUBMED: 16890833
   Comments:Similar to the DRV studies, pts on TPV/r + an OB regimen that included ENF had a better virologic response rate (VL reduction of 1.67log vs 0.98 log)
   
   
3. Lalezari JP, Henry K, O'Hearn M, et al.; Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America.; N Engl J Med; 2003; Vol. 348; pp. 2175-85;
   ISSN: 1533-4406;
   PUBMED: 12637625
   Comments:Pooled data presented to FDA from 2 randomized, controlled, open-label studies (TORO 1 and TORO 2) involving 995 treatment-experienced pts. ENF + an optimized background (OB) regimen superior to OB regimen alone. Pts had baseline VL of 5.2 logs, mean of 12 prior ART agents, and 80-90% had >5 resistance mutations to NRTIs, NNRTIs, or PIs. VL change from baseline to wk 24 was -1.52 log for pts receiving ENF + OB regimen arm compared to -0.73 log in OB arm. As expected, pts with >2 active agents in their OB regimen more likely to achieve undetectable VL.