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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 6037 [www.page-meeting.org/?abstract=6037]


Oral: Drug/Disease modelling


C-07 Lucy Hutchinson Mixed-effect modelling of transient tumour growth dynamics following anti-angiogenic therapy

L G Hutchinson (1), E A Gaffney (1), P K Maini (1), J Wagg (2), A Phipps (3), H J Mueller (4), H M Byrne (1), B Ribba (2)

(1) Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Andrew Wiles Building, Radcliffe Observatory Quarter, UK (2) Roche Pharmaceutical Research and Early Development, Clinical Pharmacology, Roche Innovation Centre Basel, Switzerland (3) Roche Pharmaceutical Research and Early Development, Clinical Pharmacology, Roche Innovation Centre Welwyn, UK (4) Roche Pharmaceutical Research and Early Development, Roche Innovation Centre Penzberg, Germany

Objectives: Anti-angiogenic (AA) therapy may give rise to a transient period where tumour blood vessels are less permeable and tortuous, and the tumour is better perfused [1][2]. Experimental evidence suggests that the efficacy of radiotherapy and chemotherapy may be enhanced during this period [3][4]. Identification of the timing of the normalization window could enable optimal design of combination therapy regimen.

Our objective is to characterize the vessel normalization window leveraging only tumour volume (TV) data in preclinical models treated with bevacizumab (BEV) and vanucizumab (VAN). To conclude, we simulate tumour response to a hypothetical cytotoxic drug administered inside and outside the inferred window.

Methods: BEV is an anti-VEGF antibody and VAN is a bispecific anti-VEGF/anti-Ang2 antibody. KPL-4 xenografted mice were randomized into control, BEV, and VAN treatment groups with n=10 per group. Each group received 5 weekly doses and tumour size measurements were taken twice per week.

We draw inspiration from seminal and recent models of tumour growth kinetics with and without AA therapies [5][6][7][8]. In our model, we assume that TV undergoes logistic growth with a dynamic carrying capacity proportional to vascular volume.

We assume that the normalized vasculature transiently improves delivery of oxygen and nutrients, enhancing tumour growth via an increased carrying capacity. For model selection and fitting, we used Monolix for a mixed effects approach that leverages TV  data. For model selection we compared the Bayesian Information Criterion (BIC) for each model, alongside visual predictive checks (VPC) and residual standard error (RSE) of population parameters and inter-individual variability (IIV).

Results: A model accounting for a transient period during which vessels deliver more oxygen and nutrients to the tumour describes the data well, as evidenced by diagnostic plots such as VPC and RSE<30% for population parameters and RSE<50% for IIV parameters.

Our simulations of the administration of a hypothetical cytotoxic drug show that the drug is more efficacious if administered during the transient window, leading to a greater reduction in TV than when it is administered outside the transient window.

Conclusions: Mixed effects modelling can be used to locate and parameterise the window of enhanced tumour growth, which may be a direct or indirect effect of the vessel normalization window, for KPL-4 xenografts leveraging only TV data. Our model predicts that cytotoxic therapy would be more efficacious if administered within the transient window.



References:
[1] Winkler F et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer cell 6(6), 553–63 (2004).
[2] Dings RPM et al. Scheduling of radiation with angiogenesis inhibitors anginex and Avastin improves therapeutic outcome via vessel normalization. Clinical cancer research : an official journal of the American Association for Cancer Research 13(11), 3395–402 (2007).
[3] Myers AL, Williams RF, Ng CY, Hartwich JE & Davidoff AM. Bevacizumab-induced tumor vessel remodeling in rhabdomyosarcoma xenografts increases the effectiveness of adjuvant onizing radiation. Journal of pediatric surgery 45(6), 1080–5 (2010).
[4] Dickson PV et al. Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered Chemotherapy. Clinical Cancer Research 13(13), 3942–3950 (2007).
[5] Simeoni M. et al. Predictive Pharmacokinetic-Pharmacodynamic Modeling of Tumor Growth Kinetics in Xenograft Models after Administration of Anticancer Agents. Cancer Research 64(3), 1094–1101 (2004). ?
[6] Rocchetti M et al. Predictive pharmacokinetic-pharmacodynamic modelling of tumor growth after administration of an anti-angiogenic agent, bevacizumab, as single-agent and combination therapy in tumor xenografts. Cancer chemotherapy and pharmacology 71(5), 1147–57 (2013). ?
[7] Wilson S et al. Modeling and predicting optimal treatment scheduling between the antiangiogenic drug sunitinib and irinotecan in preclinical settings. CPT: Pharmacometrics & Systems Pharmacology (2015).
[8] Ouerdani A, Struemper H, Suttle A, Ouellet D & Ribba B. Preclinical Modeling of Tumor Growth and Angiogenesis Inhibition to Describe Pazopanib Clinical Effects in Renal Cell Carcinoma. CPT: Pharmacometrics & Systems Pharmacology (2015).