Tumor Static Concentration Curves in Combination Therapy

Abstract

Combination therapies are widely accepted as a cornerstone for treatment of different cancer types. A tumor growth inhibition (TGI) model is developed for combinations of cetuximab and cisplatin obtained from xenograft mice. Unlike traditional TGI models, both natural cell growth and cell death are considered explicitly. The growth rate was estimated to 0.006 h(-1) and the natural cell death to 0.0039 h(-1) resulting in a tumor doubling time of 14 days. The tumor static concentrations (TSC) are predicted for each individual compound. When the compounds are given as single-agents, the required concentrations were computed to be 506 mu g center dot mL(-1) and 56 ng center dot mL(-1) for cetuximab and cisplatin, respectively. A TSC curve is constructed for different combinations of the two drugs, which separates concentration combinations into regions of tumor shrinkage and tumor growth. The more concave the TSC curve is, the lower is the total exposure to test compounds necessary to achieve tumor regression. The TSC curve for cetuximab and cisplatin showed weak concavity. TSC values and TSC curves were estimated that predict tumor regression for 95% of the population by taking between-subject variability into account. The TSC concept is further discussed for different concentration-effect relationships and for combinations of three or more compounds.

Keywords

mixture dynamics; model-based drug development; oncology; pharmacokinetic-pharmacodynamic modeling; tumor xenograft

Published in

AAPS Journal
2017, volume: 19, number: 2, pages: 456-467
Publisher: American Association of Pharmaceutical Scientists

SLU Authors

• Gabrielsson, Johan

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

Associated SLU-program

Animal health (until May 2010)

Global goals (SDG)

SDG3 Good health and well-being

UKÄ Subject classification

Pharmaceutical Sciences

Publication identifier

• DOI: https://doi.org/10.1208/s12248-016-9991-1

Permanent link to this page (URI)

https://res.slu.se/id/publ/80100