Pharmacokinetic Time Course Scaling of a Subcutaneously Administered Pegylated Peptide Conjugate for a First-in-Human Investigation

Abstract

Background and purpose: 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.

Conclusion: 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.