Publications by authors named "L Aarons"
Background: Preclinical models of cancer can be of translational benefit when assessing how different biomarkers are regulated in response to particular treatments. Detection of molecular biomarkers in preclinical models of cancer is difficult due inter-animal variability in responses, combined with limited accessibility of longitudinal data.
Methods: Nonlinear mixed-effects modelling (NLME) was used to analyse tumour growth data based on expected tumour growth rates observed 7 days after initial doses (DD7) of Radiotherapy (RT) and Combination of RT with DNA Damage Response Inhibitors (DDRi).
In this article, we present an enhanced version of Cutler's deconvolution method to address the limitations of the original algorithm in estimating realistic input and output parameters. Cutler's method, based on orthogonal polynomials, suffers from unconstrained solutions, leading to the lack of realism in the deconvolved signals in some applications. Our proposed approach incorporates constraints using a ridge factor and Lagrangian multipliers in an iterative fashion, maintaining Cutler's iterative projection-based nature.
View Article and Find Full Text PDFMixed effects modeling of radiotherapy in combination with immune checkpoint blockade or inhibitors of the DNA damage response pathway.
CPT Pharmacometrics Syst Pharmacol
November 2023
Article Synopsis
- The study focuses on optimizing dosages for radiotherapy (RT) combined with immune checkpoint blockade (ICB) and DNA Damage Response inhibitors (DDRi) to enhance treatment effectiveness and reduce toxicity.
- It introduces a mathematical model that analyzes how RT can boost the immune response, particularly through increasing cytolytic T cells targeting tumors and how DDR inhibitors can delay T cell exhaustion.
- Results show that while the combo of RT and anti-PD-L1 is most effective, decreasing anti-PD-L1 efficacy slightly could make the ATM inhibitor AZD0156 more beneficial in tri-therapy scenarios.
Clinical trials assessing the impact of radiotherapy (RT) in combination with DNA damage response pathway inhibitors (DDRis) and/or immune checkpoint blockade are currently ongoing. However, current methods for optimizing dosage and schedule are limited. A mathematical model was developed to capture the impacts of RT in combination with DDRi and/or anti-PD-L1 [immune checkpoint inhibitor (ICI)] on tumor immune interactions in the MC38 syngeneic tumor model.
View Article and Find Full Text PDFPurpose: To develop a population pharmacokinetic/pharmacodynamic model (popPKPD) of intravitreal bevacizumab treatment for neovascular age-related macular degeneration (nAMD) patients to learn about the PK/PD relationship and utilise it for dosing regimen decisions on future nAMD patients.
Methods: The Greater Manchester Avastin for Neovascularisation (GMAN) randomised clinical trial data was retrospectively utilised, and the best-corrected visual acuity (BCVA) and central macular retinal thickness (CRT, measured by optical coherence tomography) were the PD inputs to the model. Using the nonlinear mixed-effects method, the best PKPD structural model was investigated, and the clinical significance of the two different dosing treatment regimens (as-needed versus routine) was evaluated.