When studying any drug, we need to consider several factors, one of course is its pharmacodynamic profile – what does a drug to do the body, and by what mechanisms it achieves its effects. However, this analysis is only one part of the picture, another key aspect to be considered is its pharmacokinetic profile – what does the body do to the drug, namely, how is it absorbed, distributed, metabolised, excreted. A third aspect is pharmacogenetics – how our genes affect the way we respond to medications.
A clinical trial to investigate the early prediction of toxicity following chemotherapy in Ewing sarcoma using blood biomarkers and correlation with age-dependent pharmacokinetic variation started in 2014. The study closed to patient recruitment in December 2020. The Newcastle research team will now analyse the clinical samples from 120 patients that participated in this trial.
What are the aims of this research project?
• Establish pharmacokinetic profiles for vincristine, ifosfamide, doxorubicin, etoposide and cyclophosphamide in Ewing sarcoma patients and to compare the results between children, adolescents and adults.
• Validate in young people a panel of blood biomarkers of bone marrow and mucosal toxicity and develop/validate cardiac toxicity biomarker assays related to the use of doxorubicin.
• Examine genetic differences associated with drug metabolism, transport and mechanism of action and identify connections with the major acute and late toxicities observed following chemotherapy.
• Investigate potential relationships between pharmacokinetics, pharmacogenetics and biomarkers of toxicity in adolescent Ewing sarcoma patients, as compared to children and adults.
These aims are designed to test the hypothesis that age-related differences in how drugs are absorbed, distributed, metabolised, and excreted impact on the differences in toxicity and survival observed between children, teenagers and adults.
How could this project improve treatment options for Ewing sarcoma patients?
Successful completion of this project would provide a scientific basis to adjust dosing regimens and allow future treatments to be tailored for each individual Ewing sarcoma patient population.