title: Safety, tolerability, and plasma pharmacokinetics of high-strength formulations of enfuvirtide (T-20) in treatment-experienced HIV-1-infected patients.
abstract: BACKGROUND
  Enfuvirtide, a HIV-1 membrane fusion inhibitor, is the first viral entry inhibitor approved for the treatment of HIV-1 infected patients in the USA. Parenteral administration of enfuvirtide in clinical trials has been safe and has resulted in significant decreases in plasma viral load, even in the setting of extensive previous treatment and multi-drug resistance to conventional antiretroviral (ARV) therapy. Previous formulations have required two injections administered twice-daily (BID).
  
  
  OBJECTIVE
  The primary objectives of this study were to evaluate the safety, tolerability, and pharmacokinetics of two high-strength 100 mg/ml formulations of enfuvirtide (carbonate [CO(3)] and tromethamine [TRIS] buffer) and of the current formulation (50 mg/ml CO(3) formulation) at doses of 90 mg (deliverable) BID and 67.5 mg (deliverable) BID in treatment-experienced patients.
  
  
  METHODS
  This was a phase II, multi-center, open-label, sequential cross-over pharmacokinetic, efficacy, and safety study. Study design included two treatment variables; dose (90 mg or 67.5 mg BID) and formulation (A: 50 mg/ml CO(3), B: 100 mg/ml CO(3) or C; 100 mg/ml TRIS).
  
  
  RESULTS
  Forty-six treatment-experienced participants were sequentially enrolled into three treatment cohorts. All cohorts had similar safety profiles and only one patient discontinued due to an adverse event. Pharmacokinetic data indicated that the high-strength 100 mg/ml CO(3) formulation was bioequivalent to the 50 mg/ml CO(3) formulation whereas the TRIS formulation was not. At 48 weeks, 59.1%, 66.7% and 16.7% had <400 copies per milliliter HIV-1 RNA in the 90 MgCO(3), 67.5 MgCO(3) and 90 mg TRIS cohorts with median suppression of HIV-1 RNA of 2.97, 3.48, and 0.87 log(10)copies per milliliter, respectively.
  
  
  CONCLUSIONS
  Based upon bioequivalence data and the convenience and similarity in safety and virological effect with the 50 mg/ml formulation, the 100 mg/ml CO(3) formulation was selected for use in clinical efficacy studies of enfuvirtide.
authors.affiliation: Infectious Diseases Physicians Inc., 3289 Woodburn Road, Suite 200, Annandale, VA 22003, USA. dwheel@erols.com
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Lalezari
authors.forename: J Michael
authors.initials: JM
authors.lastname: Kilby
authors.forename: Joseph
authors.initials: J
authors.lastname: Wheat
authors.forename: John
authors.initials: J
authors.lastname: Delehanty
authors.forename: Ralph
authors.initials: R
authors.lastname: DeMasi
authors.forename: Indravadan
authors.initials: I
authors.lastname: Patel
authors.forename: Miklos
authors.initials: M
authors.lastname: Salgo
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology; D000328:Adult; D018791:CD4 Lymphocyte Count; D002626:Chemistry, Pharmaceutical; D015331:Cohort Studies; D018592:Cross-Over Studies; D000077560:Enfuvirtide; D005260:Female; D015700:HIV Envelope Protein gp41 / Q000627:therapeutic use* / Q000633:toxicity; D023581:HIV Fusion Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D015497:HIV-1; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D018579:Patient Selection; D010446:Peptide Fragments / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D012367:RNA, Viral / Q000097:blood; D012449:Safety; D019562:Viral Load
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D012367:RNA, Viral; D000077560:Enfuvirtide