In many patients drugs do not show the expected efficacy, whereas in other patients they cause toxic effects, sometimes even at low dose. Response rates to major classes of drugs range from 25 to... Show moreIn many patients drugs do not show the expected efficacy, whereas in other patients they cause toxic effects, sometimes even at low dose. Response rates to major classes of drugs range from 25 to 60 percent. For some patients, the reason for this variability may be explained by genetic variation. Pharmacogenetics is the study of variations in DNA sequence as related to drug response. The ultimate goal of pharmacogenetics is to predict and thereby improve drug response in the individual patient. The concept of interindividual differences in drug response was proposed as early as 1909. With the completion of the Human Genome Project in 2003 hope was raised that pharmacogenetics could be implemented in clinical practice in the near future. However, the clinical use of pharmacogenetic testing remained limited. Yet, the body of evidence supporting its usefulness is growing continuously. The research presented in this thesis aims to identify the reasons for the slow clinical translation of pharmacogenetics and to explore and expand possible solutions to address these obstacles. The thesis is divided into four parts. First, obstacles and possible solutions for the clinical implementation of pharmacogenetics are identified. In the second part, issues related to the quality control of pharmacogenetic testing are discussed. In the third part, the influence of genetic variation on the response to sulfonylureas is used as a case model to investigate the possibilities for pharmacogenetics in primary care. The fourth part contains the general discussion and a future outlook. Show less
Even though treatment of several types of solid tumors has improved in the past few years with the introduction of the monoclonal antibodies against the epidermal growth factor receptor (EGFR) and... Show moreEven though treatment of several types of solid tumors has improved in the past few years with the introduction of the monoclonal antibodies against the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), the clinical benefit of these targeted therapies is modest. Pharmacogenetics has the potential to select patients with higher chance of response to agents that target these pathways. In the thesis, we describe the association of the FCGR3A Phe158Val polymorphism with progression-free survival in advanced colorectal cancer patients treated with cetuximab added to chemotherapy and bevacizumab. Following this finding, we found that cetuximab activates type 2 macrophages, which could have a negative effect on the clinical efficacy of cetuximab. Furthermore, we detected a genetic interaction profile consisting of the VEGF +405G>C and TYMS TSER polymorphisms, that was associated with the efficacy of capecitabine, oxaliplatin and bevacizumab in advanced colorectal cancer patients. Finally, we performed a genome wide association study with the same treatment, in which polymorphisms in the proximity of the AGPAT5 gene were associated with progression-free survival Show less
Calcineurin inhibitors are crucial in the prevention of acute rejection in the first year after renal transplantation. Unfortunately, these drugs (ciclosporin A, tacrolimus) are characterized by... Show moreCalcineurin inhibitors are crucial in the prevention of acute rejection in the first year after renal transplantation. Unfortunately, these drugs (ciclosporin A, tacrolimus) are characterized by serious clinical toxicity and between patient variability in their effect. Therefore, the dose of these drugs should be individualized in order to reach a balance between rejection and toxicity. This thesis aimed to describe the variability between and within patients using mathematical models and subsequently to explain this variability. Genetic and non-genetic factors were used to explain variability and several factors were identified (polymorphism in metabolism enzyme CYP3A5, body weight, concomitant prednisolone dose). For this purpose drug concentrations in blood are measured as a concentration biomarker. Furthermore, another biomarker the activity ot the target enzyme calcineurin was determined in leukocytes, but was found to be more variable within patients than between patients. This response biomarker was not found to be clinically useful to individualize the drug dosage. Finally, pharmacological determinants for subclinical acute rejection at 6 months were determined in patients treated with ciclosporin. Although ciclosporin exposure and several genetic variants were not found to relate, a previous acute rejection period and a kidney from a deceased donor increased the risk of rejection 5-fold. Show less
