DDMODEL00000230: A pharmacokinetic model for interleukin-21 therapy validated prospectively in murine experiments in melanoma
This is a semi-mechanistic PK model for immunotherapy by a cytokine-based drug, interleukin (IL)-21, administered for solid tumors (i.e. metastatic melanoma, renal cell carcinoma). IL-21 affects the dynamics of various cellular entities toward creating a favored adaptive immune response, i.e. drives the proliferation of CTLs while lowering the survival of NK cells. At the same time, IL-21 boosts the killing capabilities of each of these effector cells, by increasing the levels of the intracellular cytotoxic proteins that mediate tumor cell lysis. The system comprises seven equations descibing drug pharmacokinetics for three different modes of administration. The model was originally trained and validated on data from several independent in vivo experiments in mice treated with IL-21 by various administration strategies (i.e. genetically-modified IL-21-secreting tumor cells termed cytokine gene therapy, IL-21-encoding plasmids termed hydrodynamics-based gene therapy, and recombinant murine IL-21 given systemically as in the clinic). The present version of the model was slightly modified for the DDMoRe platform, and the parameters were estimated in Monolix 3.2. The analysis of the model in the original study showed that IL-21 dose reduction and regimen fractionation are beneficial for obtaining substantial reductions in the tumor mass. The IL-21 mechanism of action in the studied murine setting seems to be very similar to that observed in clinical trials in solid cancer patients treated by IL-21. Thus, following a relatively straightforward up-scaling process to the human system, the model can be helpful for optimizing IL-21 systemic therapy in the clinic.
|Context of model development:||Mechanistic Understanding; Dose & Schedule Selection and Label Recommendation;|
|Discrepancy between implemented model and original publication:||The model was simplified by removing one of the compartments and the parameters were estimated using Monolix;|
|Model compliance with original publication:||No;|
|Model implementation requiring submitter’s additional knowledge:||No;|
|Modelling context description:||This is PK model of IL-21 in mice, encompassing three different, modes of drug administration.;|
|Modelling task in scope:||simulation; estimation;|
|Nature of research:||In vivo; Fundamental/Basic research; Discovery stage;|
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- Model owner: Moran Optimata
- Submitted: Nov 1, 2016 11:02:14 AM
- Last Modified: Nov 1, 2016 11:02:14 AM
Independent variable T
Structural Model sm
Continuous / Residual Data
Estimation Step estimStep_1
Initial estimates for non-fixed parameters
1) Estimate the population parameters