title: Pharmacokinetics of plasma enfuvirtide after subcutaneous administration to patients with human immunodeficiency virus: Inverse Gaussian density absorption and 2-compartment disposition.
abstract: OBJECTIVE
  Enfuvirtide (T-20) is the first of a novel class of human immunodeficiency virus (HIV) drugs that block gp41-mediated viral fusion to host cells. The objectives of this study were to develop a structural pharmacokinetic model that would adequately characterize the absorption and disposition of enfuvirtide pharmacokinetics after both intravenous and subcutaneous administration and to evaluate the dose proportionality of enfuvirtide pharmacokinetic parameters at a subcutaneous dose higher than that currently used in phase III studies.
  
  
  METHODS
  Twelve patients with HIV infection received 4 single doses of enfuvirtide separated by a 1-week washout period in an open-label, randomized, 4-way crossover fashion. The doses studied were 90 mg (intravenous) and 45 mg, 90 mg, and 180 mg (subcutaneous). Serial blood samples were collected up to 48 hours after each dose. Plasma enfuvirtide concentrations were measured with use of a validated liquid chromatography-tandem mass spectrometry method.
  
  
  RESULTS
  Enfuvirtide plasma concentration-time data after subcutaneous administration were well described by an inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment. The model-derived mean pharmacokinetic parameters (+/-SD) were volume of distribution of the central compartment (3.8 +/- 0.8 L), volume of distribution of the peripheral compartment (1.7 +/- 0.6 L), total clearance (1.44 +/- 0.30 L/h), intercompartmental distribution (2.3 +/- 1.1 L/h), bioavailability (89% +/- 11%), and mean absorption time (7.26 hours, 8.65 hours, and 9.79 hours for the 45-mg, 90-mg, and 180-mg dose groups, respectively). The terminal half-life increased from 3.46 to 4.35 hours for the subcutaneous dose range from 45 to 180 mg.
  
  
  CONCLUSIONS
  An inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment was appropriate to describe complex absorption and disposition kinetics of enfuvirtide plasma concentration-time data after subcutaneous administration to patients with HIV infection. Enfuvirtide was nearly completely absorbed from subcutaneous depot, and pharmacokinetic parameters were linear up to a dose of 180 mg in this study.
authors.affiliation: Department of Clinical Pharmacology, Hoffmann-La Roche Inc, Nutley, NJ 07110, USA. xiaoping.zhang@roche.com
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.forename: Keith
authors.initials: K
authors.lastname: Nieforth
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Lang
authors.forename: Regine
authors.initials: R
authors.lastname: Rouzier-Panis
authors.forename: Jacques
authors.initials: J
authors.lastname: Reynes
authors.forename: Albert
authors.initials: A
authors.lastname: Dorr
authors.forename: Stanley
authors.initials: S
authors.lastname: Kolis
authors.forename: Mark R
authors.initials: MR
authors.lastname: Stiles
authors.forename: Tosca
authors.initials: T
authors.lastname: Kinchelow
authors.forename: Indravadan H
authors.initials: IH
authors.lastname: Patel
mesh_terms: D000042:Absorption; D000328:Adult; D000465:Algorithms; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D000077560:Enfuvirtide; D005260:Female; D015700:HIV Envelope Protein gp41 / Q000008:administration & dosage; D015658:HIV Infections / Q000378:metabolism*; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D016011:Normal Distribution; D010446:Peptide Fragments / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; D000077560:Enfuvirtide