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Potentiation of Anticancer Antibody Efficacy by Antineoplastic Drugs: Detection of Antibody-drug Synergism Using the Combination Index Equation
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Tumor Static Concentration Curves in Combination Therapy.

Tim Cardilin1,2, Joachim Almquist3,4, Mats Jirstrand3

  • 1Fraunhofer-Chalmers Centre, Chalmers Science Park, Gothenburg, Sweden. tim.cardilin@fcc.chalmers.se.

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|September 30, 2016
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Summary

A new tumor growth inhibition model explicitly considers natural cell growth and death. This model predicts effective combination therapy concentrations for cetuximab and cisplatin, crucial for cancer treatment strategies.

Keywords:
mixture dynamicsmodel-based drug developmentoncologypharmacokinetic-pharmacodynamic modelingtumor xenograft

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Area of Science:

  • Pharmacology
  • Mathematical Biology
  • Oncology

Background:

  • Combination therapies are standard for treating various cancers.
  • Existing tumor growth inhibition (TGI) models often overlook natural cell death and growth dynamics.

Purpose of the Study:

  • To develop a novel TGI model that explicitly incorporates natural cell growth and death.
  • To predict tumor static concentrations (TSC) for cetuximab and cisplatin combinations in xenograft mice.
  • To analyze the impact of drug combinations on tumor regression and identify optimal concentration ranges.

Main Methods:

  • A mathematical model was developed to simulate tumor growth and cell death.
  • Tumor doubling time was calculated based on estimated growth and natural death rates.
  • Tumor static concentrations (TSC) and TSC curves were predicted for cetuximab and cisplatin, individually and in combination.
  • Between-subject variability was incorporated to predict tumor regression for 95% of the population.

Main Results:

  • The model estimated a tumor growth rate of 0.006 h⁻¹ and a natural cell death rate of 0.0039 h⁻¹, resulting in a 14-day tumor doubling time.
  • Single-agent TSCs were determined as 506 μg·mL⁻¹ for cetuximab and 56 ng·mL⁻¹ for cisplatin.
  • The TSC curve for cetuximab and cisplatin exhibited weak concavity, indicating specific concentration combinations for tumor shrinkage versus growth.
  • Estimated TSC values predict tumor regression for 95% of the population when considering variability.

Conclusions:

  • The developed TGI model provides a more comprehensive understanding of combination therapy effects by including cell growth and death.
  • The TSC concept and derived curves are valuable for optimizing drug concentrations in combination cancer treatments.
  • The findings support the application of this modeling approach for predicting efficacy and guiding therapeutic strategies for cetuximab and cisplatin combinations.