PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe.
PAGE 25 (2016) Abstr 5736 [www.page-meeting.org/?abstract=5736]
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Oral: Methodology - New Modelling Approaches
Martin Fink (1), Philip J Lowe (1), Vittal Shivva (2)
(1) Novartis Pharma AG, Basel, Switzerland; (2) University of Otago, Dunedin, New Zealand
Objectives: Obtaining a good prior for the linear PK part of new monoclonal antibodies (mAb) is essential for designing first-in-man (FIM) studies but also for fitting possible non-linear target-mediated disposition observed in these studies early-on.
Methods: Non-human primate (NHP) studies and FIM studies for six mAbs were fitted with 2cmt PK models, first separately, later together using a simple pool, a model with a 3rd hierarchical random effects ($LEVEL, NM7.3+) and a model including covariates for between mAb differences. Two other mAbs with slightly nonlinear PK were included for comparison.
Results: There was good agreement between compounds for the central volume (reflecting the rapidly accessible plasma volume Vp of 2.9L for a 70kg man), but the tissue volume (Vti) and clearance (CL) differed substantially – leading to terminal half-lives ranging from 15 to 28 days (plausibly due to differences in FcRn binding, charge distribution, glucolysation, etc. – see e.g., [1,2]). Inter-compartmental flow estimates were variable but mostly with poor precision.
Conclusions: Ignoring inter-mAb variation leads to inflated estimates of IIV. However, by using just the terminal half-life estimates from NHP data one can account for between-mAb-differences in human and thus provide non-inflated priors for the linear PK of new mAbs.