title: Pharmacokinetic Time Course Scaling of a Subcutaneously Administered Pegylated Peptide Conjugate for a First-in-Human Investigation.
abstract: OBJECTIVE
  Predicting absorption of macromolecules in humans following subcutaneous administration is complicated by interspecies differences in skin anatomy. The objective of this research was to test the hypothesis that an empiric relationship exists between non-human primates (NHPs) and humans in the absorption of a subcutaneously administered macromolecule which was then used to predict the time course of a pegylated peptide conjugate for planning of a first-in-human investigation.
  
  
  METHODS
  Concentration data obtained from NHPs receiving intravenous and subcutaneous doses of a novel pegylated peptide conjugate were fit to a pharmacokinetic model. The model was then scaled to a virtual population of humans through incorporation of allometric scaling factors on clearance, volume and first-order rate absorption processes. Several scenarios of simulated data were compared with observed data obtained from a first-in-human investigation.
  
  
  RESULTS
  NHP data were best described by a 2-compartment model with dual-parallel, first-order absorption processes, one of which exhibited a lag time. Empirically selected scaling factors, assuming an inverse relationship of body weight and absorption provided reasonable prediction of the peptide's time course in plasma. Employing fitted exponents based on observed human data improved the fit somewhat, however, did not correct entirely for over prediction observed with the empiric exponents.
  
  
  CONCLUSIONS
  For macromolecules where the absorption can be described by first-order rate processes, an assumption of an inverse relationship in species size may predict the time course after subcutaneous administration and may support optimal study design for a first-in-human investigation.
authors.affiliation: School of Pharmacy, University of Waterloo, 200 University Ave W, Waterloo, ON, N2L 3G1, Canada.
authors.forename: Elliot
authors.initials: E
authors.lastname: Offman
authors.affiliation: School of Pharmacy, University of Waterloo, 200 University Ave W, Waterloo, ON, N2L 3G1, Canada. aedginto@uwaterloo.ca.
authors.forename: Andrea N
authors.initials: AN
authors.lastname: Edginton
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D010455:Peptides / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000493:pharmacokinetics; D065566:Subcutaneous Absorption
chemical_list: D010455:Peptides; D011092:Polyethylene Glycols
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