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Lewis Sheiner


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 23 (2014) Abstr 3125 [www.page-meeting.org/?abstract=3125]


Poster: Drug/Disease modeling - Other topics


II-07 Kha Le Population PKPD Modeling of Geographic Atrophy Disease Progression, Target Mediated Disposition and Treatment Effect of Lampalizumab

Kha Le (1), Leonid Gibiansky (2), Erich Strauss (1), Zhengrong Li (1), Menno van Lookeren (1), Brian Yaspan (1), Jin Jin (1), Jennifer Visich (1)

(1) Genentech, (2) Quantpharm LLC.

Objectives: To develop a population based model to understand geographic atrophy (GA) disease progression, PKPD relationship and the therapeutic effect of lampalizumab (anti-factor D) using data from the Phase Ib/II MAHALO study.

Methods: The PK, PD and efficacy data were obtained from a phase Ib/II, multicenter, randomized, single-masked, sham injection-controlled study of intravitreal administration of lampalizumab in patients with GA. The PKPD analysis used a nonlinear mixed effect modeling approach. The modeling was performed using a target mediated drug disposition (TMDD) model fitting serum and aqueous humor total lampalizumab and factor D (FD) data. The longitudinal natural GA disease progression and treatment effect of lampalizumab were modeled simultaneously using all patient data. Covariate analysis was performed to identify factors influencing the disease progression, and the drug dependent treatment effect.  Simulations were performed to evaluate the predictive performance of the PKPD model.

Results: A combined ocular/serum TMDD model using quasi steady state approximation that takes into account fast turnover kinetics of FD in the eye, first-order drug clearance, complex internalization and transfer rate between ocular and serum tissues was shown to adequately describe the PKPD data. The natural GA disease progression measured by GA area as visualized by fundus auto-fluorescence imaging was well described by a linear growth model. The therapeutic effect of lampalizumab can be adequately described by a linear relationship between vitreous lampalizumab concentration and the slope of disease progression with time. A common variant previously associated with risk of age-related macular degeneration at the Complement factor I (CFI) locus was a significant covariate for both disease progression rate and lampalizumab treatment effect.

Conclusions: A population PKPD-efficacy model was developed to describe the longitudinal disease progression of GA, the disposition and treatment effect of lampalizumab. This model was used for evaluation of different dosing strategies. 



References:
[1] Do DV, Pieramici DJ, van Lookeren Campagne M, Beres T, Friesenhahn M, Zhang Y,Strauss EC. Phase Ia Investigators. A phase ia dose-escalation study of the anti-factor D monoclonal antibody fragment FCFD4514S in patients with geographic atrophy. Retina. 2014 Feb;34(2):313-20.
[2] Williams DF, Yaspan B, Li Z, Dressen A, Beres T, Le K, Henry E, Ho C, Strauss EC. American Society of Retina Specialists (ASRS) 31st Annual Meeting: Toronto, Ontario, Canada, August 27 2013.