Personalised Medicine in the Treatment of Cancer

Abstract

Understanding of pharmacokinetic-pharmacodynamic relationship for a given drug, and factors determining this, is an important part of personalised medicine in terms of choosing the correct regimen and maximising the therapeutic benefit with minimal toxicity. In the field of cancer, diversity of disease characteristics, complexity of regimens, as well as limited understanding of PK-PD profiles of rapidly-progressing anticancer drugs, create challenges for clinicians and patients to achieve the optimal outcome. This thesis addresses areas of cancer treatment where there is a need for identification of pharmacokinetic (PK), pharmacogenetic (PG) or physiological contributors, which may explain the observed variability, pharmacokinetics or toxicity of the studied drugs. The first component of the work aimed to investigate pharmacogenetic factors determining pharmacokinetics of actinomycin D. The study involves identification of the candidate transporters through in vitro uptake assays, which then led to clinical PK-PG analysis to determine clinically-significant transporter genotype influencing actinomycin D pharmacokinetics. The second component of the work explores pharmacodynamic associations between toxicity (pyrexia: body temperature > 38C) and exposure to dabrafenib and trametinib (CombiDT) used in the treatment of patients with melanoma expressing the common BRAF V600E/K mutation. A biomarker analysis using a panel of cytokines was also conducted to investigate their role in predicting or indicating the incidence of this toxicity. The significant findings of our study include identification of involvement of Solute Carrier (SLC) transporters (OAT4 and PEPT2) in actinomycin D uptake in vitro and the potentially predictive role of cytokines (IL-1B and IL-6) in CombiDT-induced pyrexia. Some of the results, such as the role of SLC transporters in clinical pharmacokinetics of actinomycin D in paediatric cancer patients, and drug exposure-pyrexia relationship for CombiDT treatment, lacked definitive conclusions due to study limitations, and provide areas of further research. Overall, we believe that our study has made valuable contributions to the enhanced understanding of these drugs, and a step closer to personalised medicine in the treatment of cancer.