My Profile

Search abstracts

Lewis Sheiner


2018
Montreux, Switzerland



2017
Budapest, Hungary

2016
Lisboa, Portugal

2015
Hersonissos, Crete, Greece

2014
Alicante, Spain

2013
Glasgow, Scotland

2012
Venice, Italy

2011
Athens, Greece

2010
Berlin, Germany

2009
St. Petersburg, Russia

2008
Marseille, France

2007
KÝbenhavn, Denmark

2006
Brugge/Bruges, Belgium

2005
Pamplona, Spain

2004
Uppsala, Sweden

2003
Verona, Italy

2002
Paris, France

2001
Basel, Switzerland

2000
Salamanca, Spain

1999
Saintes, France

1998
Wuppertal, Germany

1997
Glasgow, Scotland

1996
Sandwich, UK

1995
Frankfurt, Germany

1994
Greenford, UK

1993
Paris, France

1992
Basel, Switzerland



Printable version

PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe.
ISSN 1871-6032

Reference:
PAGE 25 (2016) Abstr 5736 [www.page-meeting.org/?abstract=5736]


PDF poster/presentation:
Click to open Click to open

Oral: Methodology - New Modelling Approaches


C-15 Martin Fink Improving priors for human mAb linear PK parameters by using half-lives from pre-clinical studies

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.
One of the two nonlinear compounds showed, despite similar typical parameter values, greater inter-individual variability (IIV) in Vti (47 %CV) whereas the other showed much larger CL, Vp and Vti, perhaps due to rapid binding to readily available membrane-bound receptors.
The simple pool of human studies (similar to [3]) gave larger IIV estimates (CL 32 %CV, Vti 35 %CV) than the separate fits (CL 13-26 %CV, Vti 10-36 %CV); as inter-mAb-variability was being added to the IIV. The pool using a 3rd hierarchical random effect and adding drug specific covariates gave IIV estimates close to those of the separate fits (CL 23 %CV, Vti 23 %CV).
The between-mAb differences were predictable using allometric scaling and terminal half-life estimates from NHP, which showed less than 13% difference from their respective human estimates (consistent with [4]).

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.



References:
[1] Suzuki et al., Importance of Neonatal FcR in Regulating the Serum Half-Life of Therapeutic Proteins Containing the Fc Domain of Human IgG1: A Comparative Study of the Affinity of Monoclonal Antibodies and Fc-Fusion Proteins to Human Neonatal FcR, J Immunol 2010.
[2] Datta-Mannan et al., The interplay of non-specific binding, target-mediated clearance and FcRn interactions on the pharmacokinetics of humanized antibodies, mAbs 2015.
[3] Davda et al., A model-based meta-analysis of monoclonal antibody pharmacokinetics to guide optimal first-in-human study design, mAbs 2014.
[4] Zhao et al., Across-Species Scaling of Monoclonal Antibody Pharmacokinetics Using a Minimal PBPK Model, Pharm Res 2015.