Highlights
- •We developed innovative model combining evolutionary dynamics and pharmacokinetics.
- •We adopted modeling method to simulate resistance which is difficult to achieve in vivo experiments.
- •The results indicate increasing the dose or shortening the doses interval can promote drug resistance.
- •The parameters are derived from clinical trials, so the conclusion is reliable.
Abstract
Purpose
The identification of optimal drug administration schedules to overcome the emergence
of resistance that causes treatment failure is a major challenge in cancer research.
We report the outcomes of a computational strategy to assess the dynamics of tumor
progression as a function of time under different treatment regimens.
Methods
We developed an evolutionary game theory model that combined Lotka-Volterra equations
and pharmacokinetic properties with 2 competing cancer species: nivolumab-response
cells and Janus kinase (JAK1/2) mutation cells. We selected 3 therapeutic schemes
that have been tested in the clinical trials: 3 mg/kg Q2w, 10 mg/kg Q2w, and 480 mg
Q4w. The simulation was performed under the intervals of 75, 125, and 175 days, respectively,
for each regimen. The data sources of the pharmacokinetic parameters used in this
study were collected from previous published clinical trials. Other parameters in
the evolutionary model come from the existing references.
Findings
Predictions under various dose schedules indicated a strong selection for nivolumab-independent
cells. Under the 3 mg/kg dose strategy, the reproduction rate of JAK mutation cells
was highest, with strongest tumor elimination ability at a 75-day interval between
treatments. Prolonged drug intervals to 125 or 175 days delayed tumor evolution but
accelerated tumor recurrence. Although 10 mg/kg Q2w had an obvious clinical effect
in a short time, it further promotes the progress of resistant population compared
with the 3 mg/kg dose. Our model suggests that 480 mg Q4w would be more valuable in
terms of clinical efficacy, but complete resistant occurs earlier regardless the interval.
Implications
The results of this study emphasize that increasing the dose or shortening the interval
between doses accelerates the evolution of heterogeneous populations, although the
short-term effect is significant. In practice, the therapeutic regimen should be balanced
according to the evolutionary principle.
Key words
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Article info
Publication history
Published online: November 12, 2021
Accepted:
October 6,
2021
Identification
Copyright
© 2021 Elsevier Inc.
