Pharmacogenomics (PGx) is widely recognized as an important aspect in personalizedMedicine. By analyzing and interpreting one’s genetic profile dose and drug adjustmentscan be made. In this way,... Show morePharmacogenomics (PGx) is widely recognized as an important aspect in personalizedMedicine. By analyzing and interpreting one’s genetic profile dose and drug adjustmentscan be made. In this way, one can strive to improve the safety and efficacy of drugtreatments. Nonetheless, not all genetic variability in drug response can be explained withcurrent PGx. In this thesis we explore the role of additional genetic factors which can explain this missing heritability. Firstly, rare and novel variants which are unaccounted for in routine PGx panels might play a role. Secondly, the complexity of pharmacogenes can result in an inability tounravel the genetic make-up of these genes. Thirdly, haplotype phasing is generally nottaken into account in PGx. Fourthly, all genetic variants are currently summarized intoone of four metabolic categories: poor metabolizers (PM), intermediate metabolizers(IM), normal metabolizers (NM) (previously EM) and ultra-rapid metabolizers (UM).However, enzyme activity is not a matter of ‘on’ or ‘off ’, but is more of a continuous scale.Finally, the effect of a genetic variant on drug metabolism shows substrate specific effects.This substrate specificity can result in erroneous extrapolation of variant effects to theentire range of substrates. The development of novel technologies to determine one’sgenetic make-up is evolving rapidly, thereby providing opportunities for the field of PGxto address these issues. In this thesis we show that by using long-read sequencing or trio-based sequencing more information can be obtained which can lead to a better understanding of the (rare) variants and can help with haplotype phasing. Moreover, we have shown that by combining long-read sequencing with artificial intelligence a substantial increase in explained variability can be achieved. Show less
Pharmacogenomics (PGx) utilizes an individual’s germline genetic profile to identify those who are at higher risk for ADRs or lack of efficacy. This information can be used by healthcare... Show morePharmacogenomics (PGx) utilizes an individual’s germline genetic profile to identify those who are at higher risk for ADRs or lack of efficacy. This information can be used by healthcare professionals (HCPs) to guide dose and drug selection before drug initiation in an effort to optimize drug therapy through precision medicine. Despite both the promise of and the progress in the field of PGx to achieve precision medicine, it is still not routinely applied in patient care. As such, a number of barriers preventing implementation have been identified. These include the undetermined model for delivering PGx, the lack of evidence supporting a PGx panel approach and the lack of tools supporting implementation. Therefore, the work of this thesis aims to support the implementation of precision medicine using PGx panel testing. It reports on generating evidence for PGx panel testing (Part I) and the development of tools facilitating implementation (Part II), evaluates the implementation process utilizing these tools (Part III) and quantifies the impact of PGx implementation on patient outcomes and cost-effectiveness (Part IV). Show less
Fluoropyrimidines, such as 5-fluorouracil (5-FU) and capecitabine, are among the most frequently prescribed anticancer drugs. They are inactivated by the enzyme dihydropyrimidine dehydrogenase (DPD... Show moreFluoropyrimidines, such as 5-fluorouracil (5-FU) and capecitabine, are among the most frequently prescribed anticancer drugs. They are inactivated by the enzyme dihydropyrimidine dehydrogenase (DPD). Up to 5% of the population is DPD deficient and these patients have a significantly increased risk of severe and potentially lethal toxicity when treated with regular doses of 5-FU or capecitabine. DPD is encoded by the gene DPYD and variants in DPYD can lead to a decreased DPD activity. Although prospective DPYD genotyping is a valuable tool to identify patients with DPD deficiency, and thus those at risk for severe and potential life-threatening toxicity, prospective genotyping has not yet been implemented in daily clinical care.With this thesis we improved knowledge on different aspects of DPYD genotyping and DPD phenotyping, in order to better predict DPD deficient patients and personalize their therapy. In addition, we improved clinical implementation of DPYD genotyping, and reduced the risk of severe fluoropyrimidine-induced toxicity in DPYD variant allele carriers. Show less
The aim of this thesis is to investigate the adoption of PGx and the integration of genotype guided dosing in the workflow of physicians and pharmacists in primary care. This thesis is divided into... Show moreThe aim of this thesis is to investigate the adoption of PGx and the integration of genotype guided dosing in the workflow of physicians and pharmacists in primary care. This thesis is divided into five parts. The first part provides an overview of answers to frequently asked questions by clinicians related to the implementation of PGx. The second part of this covers investigates whether genotype guided dosing in primary care is feasible in a pilot study where 200 patients with an incident prescription for a subset of 10 drugs and historical use are genotyped in a panel based approach for 8 pharmacogenes and received genotype guided dosing based on recommendations of the DPWG guidelines and covers an assessment of the clinical impact of PGx in primary care in the Netherlands is provided to predict how many patients that start with a drug currently described in the guidelines of the DPWG require an optimization of therapy. Part III covers the harmonization of PGx-test interpretation and therapeutic recommendations. Part IV investigates the knowledge, experience and attitudes towards PGx among (future) healthcare professionals. The thesis is concluded with a general discussion. Show less
Adverse drug reactions are problematic for both society and pharmaceutical industry. The costs are high in severe cases: for pharmaceutical companies due to the loss of income if a drug needs to be... Show moreAdverse drug reactions are problematic for both society and pharmaceutical industry. The costs are high in severe cases: for pharmaceutical companies due to the loss of income if a drug needs to be removed from the market; for society due to the extra healthcare that is required to treat the affected individuals. Liver damage upon drug intake is the most common type of adverse drug reaction and reason for drug withdrawal. What makes the liver such a vulnerable target is its role as the main drug-metabolizing organ and its large amount of stationary immune cells. This results in frequent exposure to drug metabolite-induced and inflammatory stress. In this thesis I have investigated the role of the signaling induced by the pro-inflammatory cytokine TNF_ in the exacerbation of drug-induced liver injury using an in vitro liver cell model. Using this model and methods such as high content imaging, gene array analysis and functional genomics we have gotten closer to understanding the molecular mechanisms of liver injury. This knowledge can be used to design novel tests for the drug-industry to assess the toxicity of novel drug candidates as well as to pin-point potentially susceptible individuals. Show less
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
Steeghs, N.; Mathijssen, R.H.J.; Wessels, J.A.M.; Graan, A.J. de; Straaten, T. van der; Mariani, M.; ... ; Guchelaar, H.J. 2011
Results from this thesis have elucidated potential genetic markers, which were associated with treatment outcome to MTX and adalimumab. Furthermore, a model for predicting the efficacy of MTX in... Show moreResults from this thesis have elucidated potential genetic markers, which were associated with treatment outcome to MTX and adalimumab. Furthermore, a model for predicting the efficacy of MTX in patients with RA was validated in two cohorts indicating that predicting efficacy by a pharmacogenetic model is feasible in RA patients treated with MTX. Importantly, definitive conclusions about the role of genetic predictive factors in treatment outcome to DMARDS could not be drawn, since these results have to be further validated and replicated in future pharmacogenetic studies. Large randomized prospective studies should be planned to demonstrate its legitimate predictive and cost-effective value before a genetically individualized approach is applicable in daily clinical practice. The potential role of pharmacogenetics in the prediction of efficacy and adverse events in RA patients treated with DMARDs is presented in this thesis. Hereby, new knowledge is added to the relatively young research field of pharmacogenetics, which may hopefully lead to a better treatment strategy for RA patients Show less
