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PK/PD Modeling of Anti-Tumor Response in Xenograft Mice Receiving MetMAb, a One-Armed Monoclonal Antibody, in Combination With Tarceva®: 30 Point Master’s Project
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics Research Group)
2012 (English)Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
Abstract [en]

PK/PD Modeling of Anti-Tumor Response in Xenograft Mice Receiving MetMAb, a One-Armed Monoclonal Antibody, in Combination With Tarceva®

Ari Brekkan Viggosson

Supervisors: Brendan Bender and Andrew Hooker

Division of Pharmacometrics      30 Point Master’s Thesis           Examiner: Margareta Hammarlund-Udenaes                                             

 

Introduction: Pharmacokinetic and pharmacodynamic (PK/PD) modeling can be used in the drug development process to make predictions of treatment success.  MetMAb and Tarceva are two anti-cancer agents shown to be effective against various tumors. In in-vivo and in-vitro experiments, a combination of the two agents indicated a potential synergistic drug effect.  This analysis uses PK/PD modeling to describe the tumor response and time-to-tumor-progression (TTP) in mice receiving MetMAb and Tarceva and to evaluate the apparent synergistic effect.  Aims: 1) Develop a PK/PD model to describe the tumor response in mice receiving single agent MetMAb.  2) Develop a PK/PD model to describe the effects of a drug combination comprised of MetMAb and Tarceva. 3) Using the models, simulate time-to-progression and evaluate synergy or additivity of the combination treatment.  Methods: Data was provided from 2 preclinical studies using tumor xenograft mice.  Tumor growth inhibition models describing the tumor response were developed and fit to data using NONMEM 7 software.  Visual predictive checks of tumor growth and TTP were done to assess model performance.  Combination effect was determined through comparisons of objective function values and goodness-of-fit plots obtained from different models.    Results:  Models well described the tumor response in mice and time-to-progression outcomes.  Models were able to indicate a synergistic effect of the combination treatment and predict TTP accurately.  Conclusion: Tumor response in mice to tyrosine kinase inhibitors can be modeled using PK/PD models of tumor growth inhibition. Additionally, these models can be used to support mechanistic hypotheses of additivity or synergism for combination treatments.

Place, publisher, year, edition, pages
2012.
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-185462OAI: oai:DiVA.org:uu-185462DiVA: diva2:571903
Uppsok
Medicine
Available from: 2013-02-28 Created: 2012-11-26 Last updated: 2013-02-28Bibliographically approved

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