Vittal, Shivva, Fink, Martin and Lowe, Philip J (2021) Improving priors for human monoclonal antibody linear pharmacokinetic parameters by using half-lives from non-human primates. Journal of Pharmacokinetics and Pharmacodynamics. ISSN 15738744

Abstract

Obtaining a good prior for the linear pharmacokinetics of new monoclonal antibodies (mAbs) would be an advantage not only for designing first-in-human (FIH) studies but also for stabilizing fitting of data with non-linear target-mediated disposition models. We estimated the pharmacokinetics from FIH studies for five mAbs using a two-compartment model, both separately and together, using a simple pool, a third hierarchical level of random effects for between mAb differences and non-human-primate half-lives as a predictor covariate for said differences. There was good agreement between compounds for the rapidly accessible central volume of 2.9 L (70 kg human), but clearances and peripheral volumes differed with terminal half-lives ranging from 15 to 28 days. The simple pool of human studies gave inter-individual variability estimates of 32% coefficient of variation (CV) for clearance and 33% CV for peripheral volume, larger than for separate fits (13–26% CV and 15–35% CV for clearance and volume respectively). Using third level hierarchical random effects gave inter-individual variability estimates close to those of separate fits (24% and 16% CV respectively). The between-mAb differences became predictable if non-human primate body weight scaled terminal half-life estimates were included as covariates on clearance and peripheral volume. In conclusion, ignoring inter-mAb variation leads to inflated estimates of inter-individual variability and unrealistic simulations for FIH studies. However, by using 70 kg body weight scaled terminal half-life estimates from non-human primates one can account for between-mAb differences and provide non-inflated priors for the linear pharmacokinetic parameters of new mAbs.

Item Type:	Article
Keywords:	Allometry Bayesian priors Modelling Monoclonal antibody Pharmacokinetics Simulation
Date Deposited:	21 Jan 2021 00:45
Last Modified:	21 Jan 2021 00:45
URI:	https://oak.novartis.com/id/eprint/43415