Colorectal cancer (CRC) is often treated with chemotherapy. However, it is well known that treatment with chemotherapy comes with challenges, such as (severe) adverse events leading to loss of... Show moreColorectal cancer (CRC) is often treated with chemotherapy. However, it is well known that treatment with chemotherapy comes with challenges, such as (severe) adverse events leading to loss of quality of life, treatment discontinuation and sometimes even death. Moreover, chances for curation in the metastatic setting are low. Therefore, a large window of opportunity to improve both safety as well as efficacy of chemotherapeutic treatment for the individual patient exists. A possible approach to improve chemotherapeutic treatment for CRC patients could be the discovery, validation and implementation of new genetic biomarkers. The use of genetic biomarkers allows to identify patients that are at higher risk for severe adverse drug events and to select patients which will benefit the most from chemotherapy. The aim of this thesis was therefore to improve the safety and efficacy of chemotherapeutic drugs in patients with colorectal cancer by individualising drug dosing and choice of drug based on germline genetic biomarkers. The described studies in this thesis brought us a few steps closer to safe and effective use of chemotherapeutic drugs in the individual colorectal cancer patient. Irinotecan should no longer be administered without a UGT1A1 genotype test and a start has been made towards personalised medicine for colorectal cancer patients with peritoneal metastases. Show less
Rheumatoid arthritis (RA) is a chronic, symmetrical, autoimmune disease characterized by inflammation of the joints, as well as damage to a variety of body systems, including the skin, eyes, lungs,... Show moreRheumatoid arthritis (RA) is a chronic, symmetrical, autoimmune disease characterized by inflammation of the joints, as well as damage to a variety of body systems, including the skin, eyes, lungs, heart and blood vessels. Therefore, to prevent (potential) damage with a more favorable course of the disease, it is important to intervene both early and agressively with medication in the treatment of RA. Typically, methotrexate is used as the first treatment, possibly in conjuction with other disease-modifying antirheumatic drugs, or with prednisolone to reduce inflammation rapidly. While the treatment of RA has improved considerably in recent decades, drug treatment does not work for everyone due to toxicity or lack of responsiveness. Therefore, it is suspected that genetics plays a major role in the both efficacy and toxicity of current RA medication. The goal of this thesis is to identify the genetic factors that influence the effectiveness or toxicity of the drugs used in RA. Show less
For more than 40 years, the selective estrogen receptor modulator tamoxifen has been the cornerstone of the endocrine therapy for hormone receptor-positive breast cancer patients. However, a wide... Show moreFor more than 40 years, the selective estrogen receptor modulator tamoxifen has been the cornerstone of the endocrine therapy for hormone receptor-positive breast cancer patients. However, a wide variability in response to therapy is still observed since disease recurrence happens in nearly 30 % of breast cancer patients. Tamoxifen has a complex metabolism and it is mainly metabolized by CYP2D6 enzyme, among others, into endoxifen, the most active metabolite of tamoxifen.In the search of a manner in order to individualize endocrine therapy with tamoxifen, CYP2D6 genotyping and therapeutic drug monitoring based on endoxifen serum concentrations were proposed as potential manners to individualize tamoxifen efficacy. Both approaches have been an ongoing discussion and many studies have been published claiming both negative and positive associations. This thesis mainly focusses on CYP2D6 genotyping and endoxifen concentrations and their impact on clinical survival outcome in early breast cancer patients treated with tamoxifen. Show less
The primary objective of this thesis is to investigate the role of pharmacogenetics in predicting drug response in treatments for the autoimmune diseases: RA and SLE. For this reason, this thesis... Show moreThe primary objective of this thesis is to investigate the role of pharmacogenetics in predicting drug response in treatments for the autoimmune diseases: RA and SLE. For this reason, this thesis is divided in two parts: pharmacogenetics related with drugs used in RA and pharmacogenetics of rituximab used in SLE and other autoimmune diseases. Part 1: Pharmacogenetics of drugs used in RA MTX is the most common DMARD used in RA. However, its use is hampered by frequent adverse drug events among which gastrointestinal toxicity is most frequent. Hepatotoxicity is a relatively rare but serious adverse event related to the use of MTX and is largely unpredictable. In chapter 2 an overview is presented of the previously performed studies concerning pharmacogenetic predictive biomarkers for MTX-induced hepatotoxicity. Treatment with anti-TNF agents results in a reduction of disease activity in most RA patients. However, a substantial part of patients does not respond to this therapy for unknown reasons. It would be highly beneficial to be able to predict whether or not an individual patient responds to treatment. Chapters 4 and 5 describe the investigations on the role of different candidate SNPs related to the efficacy of the treatment with different anti-TNFs in RA. In addition, in chapter 3 a replication study is presented based on 4 polymorphisms that were found associated with anti-TNF response in RA in a previously published genomewide association study. Part 2: Pharmacogenetics of rituximab used in SLE and other autoimmune diseases In chapters 6–8 the role of different genetic variants related to the pharmacodynamics of the drug or of the diseases are evaluated to study the contribution to differences in the response to rituximab in patients with SLE and other systemic autoimmune diseases. In chapter 6, the possible involvement of the -174 IL-6 polymorphism in the clinical response to rituximab in different systemic autoimmune diseases is assessed. In chapter 7, the aim is to investigate the possible involvement of the FCGR3A-158F/V polymorphism in the clinical response to rituximab in Spanish patients with different systemic autoimmune diseases. In chapter 8, the role of G/T polymorphism at the IL2–IL21 region in the rituximab response in a cohort of SLE patient and different autoimmune disorders is analyzed. Chapter 9 provides a summary of this thesis, chapter 10 the Dutch summary (Nederlandse samenvatting), and chapter 11 the general discussion and future perspective of this thesis. 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
This thesis on systemic treatment options in soft tissue sarcomas consists of two parts. In part I, the pharmacogenetics of systemic gastro-intestinal stromal tumors (GIST) treatment is... Show moreThis thesis on systemic treatment options in soft tissue sarcomas consists of two parts. In part I, the pharmacogenetics of systemic gastro-intestinal stromal tumors (GIST) treatment is investigated. SNPs related to the pharmacokinetics and pharmacodynamics of imatinib and sunitinib have been associated to survival and to toxicity. SNPs in VEGFA and SLCO1B3 have been associated to worse progression free survival during imatinib treatment of advanced GIST. SNPs in ABCG2 and CYP1A2 have been associated with the need for dose reduction in patients receiving imatinib for GIST. A SNP in POR was associated with better progression free survival during sunitinib treatment of advanced GIST . In part II the usage of trabectedin is soft tissue sarcomas (STS) in the Netherlands is studied. Trabectedin as second line treatment of soft tissue sarcoma was compared to ifosfamide monotherapy. The Incremental Cost-Effectiveness Ratio for leiomyosarcomas and liposarcomas was at the top end of what is considered acceptable in the Netherlands. For other soft tissue sarcomas subtypes, ifosfamide dominated trabectedin. The venous access related adverse events of trabectedin have been described. The research in this thesis contributes towards personalised treatment for advanced soft tissue sarcomas. 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
This thesis examines how both genetic and more conventional epidemiological endeavors may complement research into effects of statin therapy. These include a pharmacogenetic GWAS meta-analysis... Show moreThis thesis examines how both genetic and more conventional epidemiological endeavors may complement research into effects of statin therapy. These include a pharmacogenetic GWAS meta-analysis on statin-induced HDL-C response by the Genomic Investigation of consortium, which identified CETP as a loci of interest, and two-sample Mendelian randomization studies utilizing summary level data from the GIST and other GWAS consortia on fasted blood lipids and type 2 diabetes. We additionally examine the issue of survival bias in Mendelian randomization studies. Finally, we show that intra-individual lipid variability associates with worse neurocognitive outcomes in older individuals at high risk for vascular disease, discuss its interplay with lipid-lowering treatment, and describe the literature regarding genetic factors of possible interest. 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
Sunitinib has been approved by FDA in 2006 and became the first-line treatment for patients with clear cell metastatic renal cell carcinoma (cc-mRCC) due to its dramatic improvement in... Show moreSunitinib has been approved by FDA in 2006 and became the first-line treatment for patients with clear cell metastatic renal cell carcinoma (cc-mRCC) due to its dramatic improvement in progression-free survival (PFS) and overall survival (OS) and affordable toxicity. However, the inter-individual variability of sunitinib outcomes is large. Some clinical factors, such as blood pressure, can partly predict sunitinib efficacy, but they are not enough. More insight into the genetic factors underlying sunitinib outcome could also be helpful to improve optimization of treatment. In this thesis, the relevance of single nucleotide polymorphisms (SNPs) to sunitinib treatment in (cc)-mRCC patients was investigated with regard to efficacy and toxicity.We identified SNPs in IL8,IL13, VEGFR, CYP3A5 and CTLA-4 were associated with efficacy, toxicity and clearance.Further validation in independent cohorts is need before the implementation of these genetic biomarkers into clinical practice. Show less
Sunitinib treatment requires a personalized approach, since patients can respond very differently to this drug. Pharmacogenetics may improve our ability to provide a tailored therapy by studying... Show moreSunitinib treatment requires a personalized approach, since patients can respond very differently to this drug. Pharmacogenetics may improve our ability to provide a tailored therapy by studying how genetic variations could influence drug response. The objective of this thesis was to find genetic markers that can predict toxicity and efficacy of sunitinib in patients with metastatic renal cell carcinoma. This research builds upon previous findings from candidate gene studies by testing a selection of SNPs based on plausible involvement in pharmacokinetics or pharmacodynamics of the drug of interest. We observed that SNPs located in genes involved in metabolism and drug absorption (CYP3A4, CYP3A5, and ABCB1) are potentially associated with the clearance of sunitinib and its active metabolite. In analogy to this, we confirmed SNP associations from previous studies for SNPs in CYP3A5 and ABCB1 that predict the need for dose reductions and improvement of PFS on sunitinib. Sunitinib-induced toxicity is possibly related to SNPs in CYP3A4 and CYP3A5, and in interleukin genes IL8 and IL13. VEGFR-2 (KDR) rs34231037 G-allele variant carriers were potentially associated with a favorable response to sunitinib. A GWAS learned us that SNPs in chromosome 21 are involved in sunitinib efficacy, probably by influencing drug resistance mechanisms. Show less
Electroconvulsive therapy (ECT) is the transcutaneous application of small electrical stimuli to the brain to produce generalized seizure for the treatment of selected psychiatric disorders, mostly... Show moreElectroconvulsive therapy (ECT) is the transcutaneous application of small electrical stimuli to the brain to produce generalized seizure for the treatment of selected psychiatric disorders, mostly treatment resistant depression, acute mania, and schizophrenic syndromes. Safety of ECT increases the efficacy of therapy and provides fulfillment of a series of required treatments resulting in longer treatment effect of ECT. During the last few decades, researchers have been attempting to improve the effectiveness of ECT, to learn how and why it works, and to understand its risks and adverse side effects. As a result, the safety and efficacy of ECT has been improved and its indications have been relatively defined to increase the efficiency of outcome of therapy. While there has been considerable improvement in safety features, further investigation have been done to promote both the safety and efficacy of the treatment. Such efforts could increase our knowledge on the biological mechanisms involved in effectiveness of ECT that might result in discovery of new treatments. In this dissertation, we investigate how preprocedural medications could improve the safety and efficacy of ECT and further investigated the potential role of pharmacogenetics in the efficacy of ECT and procedural side effects such as cognitive disorders. Show less
The aim of this thesis was to optimize immunosuppressive therapy, especially everolimus therapy in renal transplantation recipients by identifying pharmacological and pharmacogenetic risk factors... Show moreThe aim of this thesis was to optimize immunosuppressive therapy, especially everolimus therapy in renal transplantation recipients by identifying pharmacological and pharmacogenetic risk factors influencing pharmacokinetics, and dynamics such as side effects and patient outcome. Therapeutic Drug Monitoring (TDM) of oral immunosuppressive agents is essential to prevent toxicity and or rejection; therefore it is very important to use a reliable and accurate bioanalytical assay. Differences between the most used analytical assays of measuring everolimus in whole blood and its effect on dosing advice were investigated. TDM is performed based on either trough or AUC monitoring and pharmacogenetics might be a valuable addition to TDM. Therefore the population pharmacokinetics of everolimus in a calcineurin free regimen was investigated and predictive factors such as pharmacogenetics were evaluated. In addition a limited sampling model was developed. MTOR inhibitors are known for a variety of side effects and high dropout rates. In this thesis a comprehensive analysis was performed aimed at identifying risk factors for discontinuation and a number of serious side effects. This thesis also describes an analysis aimed at identifying risk factor associated with delayed graft function, acute rejection and subclinical rejection in patients on a cyclosporine based immunosuppressive regimen. Show less
Pharmacotherapy plays an essential role in an allogeneic hematopoietic stem cell transplantation (allo-HSCT) procedure. Busulfan and treosulfan are two alkylating agents often applied in the... Show morePharmacotherapy plays an essential role in an allogeneic hematopoietic stem cell transplantation (allo-HSCT) procedure. Busulfan and treosulfan are two alkylating agents often applied in the conditioning regimen administered prior to the allo-HSCT. Finding the right balance between efficacious conditioning and toxicity remains the challenge for both agents. A majore One of the major complications after allo-HSCT is Acute graft-versus-host disease (aGvHD). When patients are diagnosed with grade 2 or higher aGvHD, systemic treatment with high-dose glucocorticoids is started as first line treatment. However, only half of the patients respond adequately to this therapy and also in other diseases non-responsiveness to glucocorticoids has been observed. Optimization of current drug therapies in allo-HSCT holds the potential to improve the outcome and safety. The goal of this thesis is to optimize busulfan- and treosulfan-based conditioning regimens and acute GvHD treatment with glucocorticoids by applying pharmacokinetic and pharmacogenetic profiling. Studies are performed in adults and pediatric patients. Show less
Not all hormone receptor positive breast cancer patients benefit from tamoxifen treatment, but may be nonetheless exposed to its side effects (e.g. hot flashes). Tamoxifen needs bioactivation by... Show moreNot all hormone receptor positive breast cancer patients benefit from tamoxifen treatment, but may be nonetheless exposed to its side effects (e.g. hot flashes). Tamoxifen needs bioactivation by formation of the metabolite endoxifen, which is mainly catalyzed by the enzyme CYP2D6. In this thesis, we studied the variation in tamoxifen metabolism in relation to endoxifen serum concentration, tamoxifen efficacy and side effects, focusing on CYP2D6 activity and pharmacogenetics. The importance of good methodology for genotyping and endoxifen measurement was exemplified. In a large trial population, no association between CYP2D6 genotype and disease free survival or the occurence of hot flashes was found, although polymorphisms in the estrogen receptor-1 and UGT2B15 might be related to clinical outcome. Adherence, but not the concomitant use of CYP2D6 inhibiting medication was associated with breast cancer recurrence. CYP2D6 genotype and endoxifen-guided tamoxifen dose escalation led to an increase in endoxifen serum levels and a new 13C-Dextromethorphan breath test was used for phenotyping CYP2D6, which correlated well with CYP2D6 genotype and endoxifen levels. Finally, the CYP2D6 phenotype and endoxifen serum levels are currently prospectively related to breast cancer recurrence. This may lead to therapeutic drug monitoring and selection of patients who benefit most from tamoxifen. Show less
Colon cancer is the third most frequent malignancy in the Western world. Average 5 year-survival is around 70% and depends on the stage of the disease being very poor (under 10% 5-year survival)... Show moreColon cancer is the third most frequent malignancy in the Western world. Average 5 year-survival is around 70% and depends on the stage of the disease being very poor (under 10% 5-year survival) for stage IV patients and excellent (more than 90% 5 year survival) for stage I patients. The prognosis of patients with stage II varies between 80 and 60% 5-year survival. The causes of this variation remain unclear. Furthermore, the prognosis of patients with stage III has improved significantly, reaching 70% 5-year survival, since the introduction of adjuvant chemotherapy. However, still 30% of the patients with stage III disease that do not respond to chemotherapy. Therefore, reliable predictive and prognostic markers in stage II and III colon carcinoma are necessary to be able to elucidate whether a patient is going to respond to therapy or not and to be able to offer personalized treatment. In this research project, we aimed to identify predictive markers of therapy response in stage III disease and prognostic markers in stage II and III colon carcinoma. The first three chapters focus on the value of known single nucleotide polymorphisms (SNP) in genes involved in the activation, metabolism of chemotherapeutic drugs like 5-fluorouracil and oxaliplatin as well as in the repair of DNA damage caused by these drugs as predictive markers for therapy response. In the remaining chapters , the focus is placed on the identification of molecular prognostic markers in stages II and III. Several mutations in known cancer driver genes and genes involved in signal transduction have been studied. Show less
Nausea and vomiting are well known side effects related to chemotherapy. Indeed, nausea and vomiting are the most distressing side effects of chemotherapy in cancer patients. Dopamine, serotonin... Show moreNausea and vomiting are well known side effects related to chemotherapy. Indeed, nausea and vomiting are the most distressing side effects of chemotherapy in cancer patients. Dopamine, serotonin and neurokinin1 are thought to be the neurotransmitters that play role in the pathophysiology of Chemotherapy Induced Nausea Vomiting (CINV). Thus, the antagonists of those neurotransmitters are considered as prophylactic antiemetics for CINV. In the 1990s, the use of 5-Hydroxytriptamine receptor antagonists (5-HT3RAs) highly improved the patients__ response rate to antiemetic drugs. In addition, the combination of a neurokinin 1 antagonist, a 5HT3RA and a corticosteroid can further increase the response rate up by 15% in acute phase and 20% in delayed phase. Thus, the international guideline of clinical oncology recommend this combination as prophylactic antiemetic drugs in the acute phase and a combination of dexamethasone __ metoclopramide as prophylactic antiemetics in the delayed phase. However, when the standard antiemetic drug regimens are administered to patients, there are still 20-30% patients in the acute phase and 40% patients in the delayed phase experiencing CINV. Thus, there is a high interindividual variability in response to antiemetic drugs in oncology patients. Some patient characteristics such as female gender, younger patients and history of alcohol drinking could increase the risk of CINV from 20% to 70%. Therefore, individualizing of the use of antiemetics could start by considering the patient characteristics. This thesis focuses on determining the impact of CINV on QoL in Indonesian cancer patients and optimizing the prevention and treatment of CINV by exploration of pharmacogenetic biomarkers. 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
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
