caa a22 4500 605534209 CHVBK 20210128100841.0 cr unu---uuuuu 210128e20150401xx s 000 0 eng 10.1007/s10928-015-9406-4 doi (NATIONALLICENCE)springer-10.1007/s10928-015-9406-4 A PBPK workflow for first-in-human dose selection of a subcutaneously administered pegylated peptide [Elektronische Daten] [Elliot Offman, Andrea Edginton] Predicting the pharmacokinetic (PK) time course of a subcutaneously (SC) administered novel therapeutic protein using in silico approaches offers an opportunity to streamline the drug development process by facilitating selection of starting and target doses in initial human trials. Herein, we propose a workflow for predicting the human exposure time course following SC administration. Leveraging knowledge obtained following both intravenous and SC administration in monkeys, this workflow employs the development of a whole body physiologically-based pharmacokinetic (PBPK) model incorporating vascular circulation, lymphatic uptake and both renal and non-specific clearance mechanisms to predict the PK of a novel pegylated peptide. Optimization of the model was initially performed in monkeys, after which the model was scaled up to human proportion. Inclusion of a SC depot compartment allowed for precise simulation of the SC time course in monkeys. Simulated human exposure after SC administration was within approximately 20% of the observed values and successfully predicted the time course of two subsequent dosing levels. This workflow represents one of the first publications of a PBPK workflow to predict the time course of a SC administered therapeutic protein based off of a single, non-human primate species and shows promise in facilitating the dose selection in first-in-human dose escalation studies for novel protein therapeutics. Springer Science+Business Media New York, 2015 Physiologically-based pharmacokinetic model nationallicence Subcutaneous nationallicence Protein nationallicence Monkey nationallicence Human nationallicence Offman Elliot School of Pharmacy, University of Waterloo, 200 University Ave W, N2L 3G1, Waterloo, ON, Canada aut Edginton Andrea School of Pharmacy, University of Waterloo, 200 University Ave W, N2L 3G1, Waterloo, ON, Canada aut Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/2(2015-04-01), 135-150 1567-567X 42:2<135 2015 42 10928 https://doi.org/10.1007/s10928-015-9406-4 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10928-015-9406-4 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Offman Elliot School of Pharmacy, University of Waterloo, 200 University Ave W, N2L 3G1, Waterloo, ON, Canada aut NATIONALLICENCE 700 1- Edginton Andrea School of Pharmacy, University of Waterloo, 200 University Ave W, N2L 3G1, Waterloo, ON, Canada aut NATIONALLICENCE 773 0- Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/2(2015-04-01), 135-150 1567-567X 42:2<135 2015 42 10928