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On 8–9 November 2022, the European Society of Pharmacogenomics and Personalised Therapy organized its sixth biennial congress, in Belgrade, Serbia (congress website: www.sspt.rs ). The congress aimed to address the current status and future perspectives of pharmacogenomics, share latest knowledge in the field of precision medicine and showcase the implementation of clinical applications in pharmacogenomics/pharmacogenetics. The 2 day congress consisted of 17 lectures given by key-opinion leaders and included a poster session plus discussions. The meeting was a great success by generating an informal environment and enabling the exchange of information between 162 participants from 16 different countries.

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 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).

This pilot study is aimed at implementing an approach for comprehensive clinical pharmacogenomics (PGx) profiling. Fifty patients with cardiovascular diseases and 50 healthy individuals underwent whole-exome sequencing. Data on 1800 PGx genes were extracted and analyzed through deep filtration separately. Theoretical drug induced phenoconversion was assessed for the patients, using sequence2script. In total, 4539 rare variants (including 115 damaging non-synonymous) were identified. Four publicly available PGx bioinformatics algorithms to assign PGx haplotypes were applied to nine selected very important pharmacogenes (VIP) and revealed a 45–70% concordance rate. To ensure availability of the results at point-of-care, actionable variants were stored in a web-hosted database and PGx-cards were developed for quick access and handed to the study subjects. While a comprehensive clinical PGx profile could be successfully extracted from WES data, available tools to interpret these data demonstrated inconsistencies that complicate clinical application.

Purpose: The survival of patients with clear cell metastatic renal cell carcinoma (cc-mRCC) has improved substantially since the introduction of tyrosine kinase inhibitors (TKI). With the fact that TKIs interact with immune responses, we investigated whether polymorphisms of genes involved in immune checkpoints are related to the clinical outcome of cc-mRCC patients treated with sunitinib as first TKI.Experimental Design: Twenty-seven single-nucleotide polymorphisms (SNP) in CD274 (PD-L1), PDCD1 (PD-1), and CTLA-4 were tested for a possible association with progression-free survival (PFS) and overall survival (OS) in a discovery cohort of 550 sunitinib-treated cc-mRCC patients. SNPs with a significant association (P < 0.05) were tested in an independent validation cohort of 138 sunitinib-treated cc-mRCC patients. Finally, data of the discovery and validation cohort were pooled for meta-analysis.Results: CTLA-4 rs231775 and CD274 rs7866740 showed significant associations with OS in the discovery cohort after correction for age, gender, and Heng prognostic risk group [HR, 0.84; 95% confidence interval (CI), 0.72–0.98; P = 0.028, and HR, 0.73; 95% CI, 0.54–0.99; P = 0.047, respectively]. In the validation cohort, the associations of both SNPs with OS did not meet the significance threshold of P < 0.05. After meta-analysis, CTLA-4 rs231775 showed a significant association with OS (HR, 0.83; 95% CI, 0.72–0.95; P = 0.008). Patients with the GG genotype had longer OS (35.1 months) compared with patients with an AG (30.3 months) or AA genotype (24.3 months). No significant associations with PFS were found.Conclusions: The G-allele of rs231775 in the CTLA-4 gene is associated with an improved OS in sunitinib-treated cc-mRCC patients and could potentially be used as a prognostic biomarker. Clin Cancer Res; 24(10); 2350–6. ©2018 AACR.

Supplementary Table S1 Selected tagging SNPs Supplementary Figure S1 Kaplan-Meier plot for overall survival by genotype of CTLA-4 rs231775 in discovery cohort (A), validation cohort (B) and combined cohort (C). Supplementary Figure S2 The association of CTLA-4 rs231775 with CTLA-4 gene expression in multiple tissues (A) and in testis tissue (B, p=1.0Ã-10-7) using data from the Genotype-Tissue Expression (GTEx) dataset. Supplementary Figure S3 The survival curve shows the association of CTLA-4 gene expression with overall survival in patients with clear cell renal cell carcinoma (p=0.00255) through OncoLnc, which links The Cancer Genome Atlas (TCGA) survival data to mRNA expression levels (23). (low: lower 50 percentile, high: upper 50 percentile).

Aim: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan.Patients and methods: In this prospective, multicentre, non-randomised study, patients intended for treatment with irinotecan were pre-therapeutically genotyped for UGT1A1*28 and UGT1A1)93. Homozygous variant carriers (UGT1A1 poor metabolisers; PMs) received an initial 30% dose reduction. The primary endpoint was incidence of febrile neutropenia in the first two cycles of treatment. Toxicity in UGT1A1 PMs was compared to a historical cohort of UGT1A1 PMs treated with full dose therapy, and to UGT1A1 non-PMs treated with full dose therapy in the current study. Secondary endpoints were pharmacokinetics, feasi- bility, and costs.Results: Of the 350 evaluable patients, 31 (8.9%) patients were UGT1A1 PM and received a median 30% dose reduction. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical UGT1A1 PMs (P = 0.04) and was comparable to the incidence in UGT1A1 non-PMs treated with full dose therapy. Systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs was still slightly higher compared to a standard-dosed irinotecan patient cohort (difference: thorn 32%). Cost analysis showed that genotype-guided dosing was cost-saving with a cost reduction of V183 per patient.Conclusion: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan, results in a therapeutically effec- tive systemic drug exposure, and is cost-saving. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve individual patient safety. (C) 2022 The Authors. Published by Elsevier Ltd.

Contains fulltext : 290958.pdf (Publisher’s version ) (Open Access) Hepatotoxicity is a serious adverse drug reaction related to methotrexate (MTX). However, the cause of drug-induced liver injury (DILI) is still unclear and unpredictable. Genetic risk factors may predispose for MTX-DILI. Therefore, we conducted a nested case-control genome-wide association study to explore genetic risk factors associated with MTX-DILI. Seven international groups contributed blood samples and data of patients with rheumatoid arthritis who used MTX. MTX-DILI was defined as an alanine aminotransferase (ALT) level of at least three times the upper limit of normal (ULN), to increase contrast controls ALT levels did not raise above two times the ULN. Per study site, control subjects and patients with MTX-DILI (ratio 3:1) were matched for age, gender, and duration of MTX use. Patients were genotyped using Illumina GSA MD-24v1-0 and data were imputed using the 1000 Genomes reference panel. Single-nucleotide polymorphisms (SNPs) were analyzed using an additive genetic model, corrected for sex, country, and age. A P-value of ≤ 5 × 10(-8) was considered significant, whereas a P-value of ≤ 5 × 10(-6) was considered suggestive. A total of 108 MTX-DILI cases and 311 controls were included for association analysis. None of the SNPs were significantly associated with MTX-DILI. However, we found seven suggestive genetic variants associated with MTX-DILI (P-values 7.43 × 10(-8) to 4.86 × 10(-6) ). Of those, five SNPs were in the intronic protein-coding regions of FTCDNL1, BCOR, FGF14, RBMS3, and PFDN4/DOK5. Investigation of candidates SPATA9 (rs72783407), PLCG2 (rs60427389), RAVER2 (rs72675408), JAK1 (rs72675451), PTPN2 (rs2476601), MTHFR C677T (rs1801133), and into the HLA region did not show significant findings. No genetic variants associated with MTX-DILI were found, whereas suggestive SNPs need further investigation. 01 april 2023

Pharmacogenomics (PGx)-guided drug treatment is one of the cornerstones of personalized medicine. However, the genes involved in drug response are highly complex and known to carry many (rare) variants. Current technologies (short-read sequencing and SNP panels) are limited in their ability to resolve these genes and characterize all variants. Moreover, these technologies cannot always phase variants to their allele of origin. Recent advance in long-read sequencing technologies have shown promise in resolving these problems. Here we present a long-read sequencing panel-based approach for PGx using PacBio HiFi sequencing.A capture based approach was developed using a custom panel of clinically-relevant pharmacogenes including up- and downstream regions. A total of 27 samples were sequenced and panel accuracy was determined using benchmarking variant calls for 3 Genome in a Bottle samples and GeT-RM star(*)-allele calls for 21 samples..The coverage was uniform for all samples with an average of 94% of bases covered at >30×. When compared to benchmarking results, accuracy was high with an average F1 score of 0.89 for INDELs and 0.98 for SNPs. Phasing was good with an average of 68% the target region phased (compared to ~20% for short-reads) and an average phased haploblock size of 6.6kbp. Using Aldy 4, we compared our variant calls to GeT-RM data for 8 genes (CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, SLCO1B1, TPMT), and observed highly accurate star(*)-allele calling with 98.2% concordance (165/168 calls), with only one discordance inCYP2C9leading to a different predicted phenotype.We have shown that our long-read panel-based approach results in high accuracy and target phasing for SNVs as well as for clinical star(*)-alleles.

Pharmacogenetics (PGx) studies the effect of heritable genetic variation on drug response. Clinical adoption of PGx has remained limited, despite progress in the field. To promote implementation, the Dutch Pharmacogenetics Working Group (DPWG) develops evidence-based guidelines on how to optimize pharmacotherapy based on PGx test results. This guideline describes optimization of atomoxetine therapy based on genetic variation in the CYP2D6 gene. The CYP2D6 enzyme is involved in conversion of atomoxetine into the metabolite 4-hydroxyatomoxetine. With decreasing CYP2D6 enzyme activity, the exposure to atomoxetine and the risk of atomoxetine induced side effects increases. So, for patients with genetically absent CYP2D6 enzyme activity (CYP2D6 poor metabolisers), the DPWG recommends to start with the normal initial dose, bearing in mind that increasing this dose probably will not be required. In case of side effects and/or a late response, the DPWG recommends to reduce the dose and check for sustained effectiveness for both poor metabolisers and patients with genetically reduced CYP2D6 enzyme activity (CYP2D6 intermediate metabolisers). Extra vigilance for ineffectiveness is required in patients with genetically increased CYP2D6 enzyme activity (CYP2D6 ultra-rapid metabolisers). No interaction was found between the CYP2D6 and COMT genes and methylphenidate. In addition, no interaction was found between CYP2D6 and clonidine, confirming the suitability of clonidine as a possible alternative for atomoxetine in variant CYP2D6 metabolisers. The DPWG classifies CYP2D6 genotyping as being "potentially beneficial" for atomoxetine. CYP2D6 testing prior to treatment can be considered on an individual patient basis.

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the starting dose optimization of the anti-cancer drug irinotecan to decrease the risk of severe toxicity, such as (febrile) neutropenia or diarrhoea. Uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1 encoded by the UGT1A1 gene) enzyme deficiency increases risk of irinotecan-induced toxicity. Gene variants leading to UGT1A1 enzyme deficiency (e.g. UGT1A1*6, *28 and *37) can be used to optimize an individual's starting dose thereby preventing carriers from toxicity. Homozygous or compound heterozygous carriers of these allele variants are defined as UGT1A1 poor metabolisers (PM). DPWG recommends a 70% starting dose in PM patients and no dose reduction in IM patients who start treatment with irinotecan. Based on the DPWG clinical implication score, UGT1A1 genotyping is considered "essential", indicating that UGT1A1 testing must be performed prior to initiating irinotecan treatment.

Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in

The in vitro diagnostic medical devices regulation (IVDR) will take effect in May 2022. This regulation has a large impact on both the manufacturers of in vitro diagnostic medical devices (IVD) and clinical laboratories. For clinical laboratories, the IVDR poses restrictions on the use of laboratory developed tests (LDTs). To provide a uniform interpretation of the IVDR for colleagues in clinical practice, the IVDR Task Force was created by the scientific societies of laboratory specialties in the Netherlands. A guidance document with explanations and interpretations of relevant passages of the IVDR was drafted to help laboratories prepare for the impact of this new legislation. Feedback from interested parties and stakeholders was collected and used to further improve the document. Here we would like to present our approach to our European colleagues and inform them about the impact of the IVDR and, importantly we would like to present potentially useful approaches to fulfill the requirements of the IVDR for LDTs.

Pharmacogenomic drug labels in the Summary of Product Characteristics (SmPC) provide an instrument for clinical implementation of pharmacogenomics. We compared pharmacogenomic guidance by Clinical Pharmacogenetics Implementation Consortium (CPIC), Dutch Pharmacogenetics Working Group (DPWG), the US Food and Drug Administration (FDA), and by the European agencies the European Medicines Agency (EMA), College ter Beoordeling van Geneesmiddelen Medicines Evaluation Board (CBG-MEB), and Federal Institute for Drugs and Medical Devices (FIDMD), collectively assigned as EMA/FIDMD+MEB shortened as EMA/FM. Of 54 drugs with an actionable gene-drug interaction in the CPIC and DPWG guidelines, only 50% had actionable pharmacogenomic information in the SmPCs and the agencies were in agreement in only 18% of the cases. We further compared 450 additional drugs, lacking CPIC or DPWG guidance, and found 126 actionable gene-drug labels by the FDA and/or the EMA/FM. Based on these 126 drugs in addition to the 54 above, the consensus of actionable pharmacogenomic labeling between the FDA and the EMA/FM was only 54%. In conclusion, guidelines provided by CPIC/DPWG are only partly implemented into the SmPCs and the implementation of pharmacogenomic drug labels into the clinics would strongly gain from a higher extent of consensus between agencies.

Despite the nationwide availability of pharmacogenomic (PGx) guidelines in electronic medication surveillance systems in The Netherlands, PGx guided prescribing is still uncommon in primary care. We set out to investigate the adoption of pharmacist initiated PGx testing in primary care. Community pharmacists were offered a free PGx test covering 40 variants in 8 genes to test patients receiving an incident prescription (IRx) of a selection of 10 drugs. Results of the PGx test along with predicted phenotypes and a therapeutic recommendation based on the Dutch Pharmacogenetics Working Group (DPWG) guidelines were transferred to the pharmacist and physician. Adoption was defined as the percentage of eligible patients that received genotyping. From November 2014–July 2016, 200 patients were included with an adoption of 18.0%. Of the included patients 57.5% received an IRx for atorvastatin, 14.5% started with simvastatin and 28.0% received an IRx for amitriptyline, (es)citalopram, nortriptyline, or venlafaxine. 90% of the patients carried at least one actionable PGx test result in the selected PGx-panel. In 31.0% of the incident prescriptions a combination between a drug with a known gene-drug interaction and an actionable genotype was present and a therapeutic recommendation was provided. The provided recommendations were accepted by the clinicians in 88.7% of the patients. Pharmacist initiated implementation of PGx in primary care is feasible, and the frequency of actionable gene-drug interactions for the selected drugs is high.

Introduction: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30-100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride has been successfully evaluated. Areas covered: the principal pharmacogenetic and non-genetic differences in the pharmacology of tamoxifen and endoxifen are evaluated. To this end, references from PubMed, Embase or Web of Science, among others, were reviewed As non-genetic factors, important differences and similarities such age, or adherence to tamoxifen therapy are comprehensively illustrated. Additionally, since CYP2D6 genotypes are considered the main limitation of tamoxifen, many studies have investigated the association between the worsened clinical outcomes in patients with non-functional CYP2D6 genotypes. In this review, an overview of the research on this field is presented. Also, a summary describing the literature about individualizing tamoxifen therapy with endoxifen concentrations and its limitations is listed. Expert opinion: z-endoxifen hydrochloride is only investigated in the metastatic setting, still more research is required before its place in therapeutics is known. Similarly, monitoring tamoxifen efficacy based on endoxifen concentrations might not be overall recommended due to the limited evidence available.

Aim: To study the performance of a clinical pharmacogenetic model for the prediction of nonresponse in rheumatoid arthritis (RA) patients treated with methotrexate (MTX) in combination with other synthetic or biologic disease-modifying anti-rheumatic drugs . This prediction model includes gender, smoking status, rheumatoid factor positivity and four genetic variants in AMPD1 (rs17602729), ATIC (rs2372536), ITPA (rs1127354) and MTHFD1 (rs17850560). Methods: A total of 314 RA patients from three Dutch studies were retrospectively included. Eligible patients were adults diagnosed with RA and had a treatment duration with MTX and follow-up for at least two study evaluation visits. Prediction model risk scores at the first and second evaluation were calculated and compared with the actual nonresponse (disease activity score >2.4). Regression and receiver operating characteristic curve analyses of the prediction model were performed. Also, the sensitivity, specificity and the positive and negative predictive values (PPV and NPV) were determined. Results: The receiver operating characteristic area under the curve was 75% at first and 70% after second evaluation. At the second evaluation, prediction nonresponse had a sensitivity of 67% (CI: 54–78%), specificity of 69% (CI: 60–77%), PPV of 52% (CI: 45–60%) and NPV of 80% (CI: 73–85%). Conclusions: This study demonstrates that the clinical pharmacogenetic model has an inadequate performance for the prediction of nonresponse to MTX in RA patients treated with combination therapies.

BackgroundTocilizumab improves outcome, including survival, in intensive care unit (ICU) admitted COVID-19 patients. The currently applied dosage of 8 mg/kg is based on use of this drug for other indications, however is has not formally been investigated for COVID-19. In this study pharmacokinetics and dynamics of tocilizumab were investigated in ICU admitted COVID-19 patients.MethodsThis was an open-label, single-center observational pharmacokinetic and -dynamic evaluation study. Enrolled patients, with polymerase chain reaction confirmed Covid-19 were admitted to the ICU for mechanical ventilation or high flow nasal canula oxygen support. All patients were 18 years of age or older and received tocilizumab within 24 hours after admission to the ICU and received 6 mg dexamethasone daily as concomitant therapy.Results29 patients were enrolled between 15 December 2020 and 15 March 2021. A total of 139 tocilizumab plasma samples were obtained covering the pharmacokinetic curve of day 0 up to day 20 after tocilizumab initiation. A population pharmacokinetic model with parallel linear and non-linear clearance was developed and validated. Average AUC0-inf 1stDOSEwas 938 [±190] ug/mL*days. Tocilizumab half-life was estimated to be 4·15 [±0·24] days. All patients had tocilizumab exposure above 1 ug/ml for at least 15 days.ConclusionThis study provides evidence to support a fixed dose of 600 mg tocilizumab in COVID-19 patients. Furthermore our findings suggest that alternative cost saving regimens with even lower doses are likely to be as effective as the current 8 mg/kg recommendation.FundingNo external funding was received for this workBackgroundIn the randomized controlled trial REMAP-CAP, the IL-6 receptor antagonist tocilizumab was shown to improve outcome, including survival in ICU admitted COVID-19 patients. Because obesity is a risk factor for development of severe COVID-19, concerns have been raised about overtreatment as well as undertreatment through weight-based dosing of tocilizumab. Furthermore pharmacokinetic and pharmacodynamic parameters of medications are often found to be different in severely ill patients when compared to mild or moderately ill patients. However, the effects of different dosing schedules were only investigated to a very limited extent in non-randomized observational studies. Hence, evaluation of the PK/PD parameters of tocilizumab in severely ill patients – is warranted.Added value of this studyThis study provides valuable information about the population pharmacokinetics and dynamics of tocilizumab in dexamethasone cotreated ICU admitted COVID-19 patients. This research shows that there is no rationale for the 8 mg/kg dosing recommendation in ICU patients. Fixed dosing of 600 mg tocilizumab is a cost saving, logistically attractive and safe alternative without losing efficacy.Implications of all the evidenceDue to the ongoing pandemic, shortages of tocilizumab and other IL-6 receptor antagonists may be anticipated. A fixed tocilizumab dose regimen has many practical and safety advantages, e.g. it will reduce dosing errors and avoid unnecessary wastage of medication. More importantly, according to the data presented in this study, relative underdosing of patients with low, or low-normal bodyweight compared to patients with high bodyweight will be avoided. Last but not least, in view of the large number of patients currently being treated with these agents, a significant cost saving can also be expected.

Pharmacogenomics is a key component of personalized medicine that promises safer and more effective drug treatment by individualizing drug choice and dose based on genetic profiles. In clinical practice, genetic biomarkers are used to categorize patients into *-alleles to predict CYP450 enzyme activity and adjust drug dosages accordingly. However, this approach leaves a large part of variability in drug response unexplained. Here, we present a proof-of-concept approach that uses continuous-scale (instead of categorical) assignments to predict enzyme activity. We used full

Tacrolimus is metabolized by CYP3A4 and CYP3A5 enzymes. Patients expressing CYP3A5 (in Caucasian patients about 15% of the population but more frequent in African Americans and Asians) have a dose requirement that is around 50% higher than non-expressers to reach the target concentration. CYP3A5 expressers can be considered fast metabolizers. The trough concentration/dose (C-0/D) ratio of tacrolimus has recently been proposed as a prognostic marker for poor outcome after kidney transplantation. Patients with a low C-0/D ratio (also referred to as fast metabolizers) seem to have more tacrolimus-related nephrotoxicity, more BK-viremia, and a lower graft survival. At first sight, the expression of CYP3A5 and a low C-0/D ratio seem to be overlapping factors, both pointing towards patients in whom a higher tacrolimus dose is needed to reach the tacrolimus target concentration. However, there are important differences, and these differences may explain why the impact of the C-0/D ratio on long term outcome is stronger than for CYP3A5 genotype status. Patients with a low C-0/D ratio require a high tacrolimus dose and are exposed to high tacrolimus peak concentrations. The higher peak exposure to tacrolimus (and/or its metabolites) may explain the higher incidence of nephrotoxicity, BK-viremia and graft loss. A potential confounder is the concurrent maintenance treatment of corticosteroids, as steroids are sometimes continued in patients at high immunological risk. Steroids induce the metabolism of tacrolimusviapregnane X receptor mediated increased CYP3A4 expression, resulting in lower tacrolimus C-0/D ratio in high risk patients. Also non-adherence may result in lower C-0/D ratio which is also associated with poor outcome. The C-0/D ratio of tacrolimus does seem to identify a group of patients with increased risk of poor outcome after kidney transplantation. Our recommendation is to monitor tacrolimus peak concentrations in these patients, and if these are high then target slightly lower pre-dose concentrations. Another possibility would be to switch to a prolonged release formulation or to dose the drug more frequently, in smaller doses, to avoid high peak concentrations.

Introduction: HLA variants have been shown to be associated with an increased risk of hypersensitivity reactions to specific drugs. Both the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) have issued actionable HLA gene – drug interaction guidelines but diagnostic test criteria remain largely unknown. We present an overview of the diagnostic test criteria of the actionable HLA – drug pairs. Methods: A systematic literature search was conducted in PubMed, Embase, Web of Science and Cochrane Library. Original case-control and cohort studies were selected and sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and number needed to genotype (NNG) were calculated for the actionable HLA-drug pairs. Results: In general, the HLA tests show high specificity and NPV for predicting hypersensitivity reactions. The sensitivity of HLA tests shows a wide range, from 0-33% for HLA-B*1502 testing to predict lamotrigine induced SJS/TEN up to 100% for HLA-B*5701 to predict immunologically confirmed abacavir hypersensitivity syndrome (ABC-HSR). PPV is low for all tests except for HLA-B*5701 and ABC-HSR which is approximately 50%. HLA-B*5701 to predict ABC-HSR shows the lowest NNG followed by HLA-B*5801 for allopurinol induced severe cutaneous adverse drug reactions and HLA-B*1502 for carbamazepine induced SJS/TEN. Discussion: This is the first overview of diagnostic test criteria for actionable HLA-drug pairs. Studies researching HLA genes and hypersensitivity are scarce for some of the HLA-drug pairs and patient numbers in available studies are small. Therefore more research is necessary to calculate the diagnostic criteria more accurately.

Contains fulltext : 229047.pdf (Publisher’s version ) (Open Access) For ~ 80 drugs, widely recognized pharmacogenetics dosing guidelines are available. However, the use of these guidelines in clinical practice remains limited as only a fraction of patients is subjected to pharmacogenetic screening. We investigated the feasibility of repurposing whole exome sequencing (WES) data for a panel of 42 variants in 11 pharmacogenes to provide a pharmacogenomic profile. Existing diagnostic WES-data from child-parent trios totaling 1,583 individuals were used. Results were successfully extracted for 39 variants. No information could be extracted for three variants, located in CYP2C19, UGT1A1, and CYP3A5, and for CYP2D6 copy number. At least one actionable phenotype was present in 86% of the individuals. Haplotype phasing proved relevant for CYP2B6 assignments as 1.5% of the phenotypes were corrected after phasing. In conclusion, repurposing WES-data can yield meaningful pharmacogenetic profiles for 7 of 11 important pharmacogenes, which can be used to guide drug treatment.

Aims Tacrolimus and mycophenolic acid dosing after renal transplantation is individualized through therapeutic drug monitoring (TDM). Home-based dried blood spot (DBS) sampling has the potential to replace conventional TDM sampling at the clinic. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed to quantify tacrolimus and mycophenolic acid in DBS and clinically validated for abbreviated area under the concentration-time curve (AUC) monitoring using an innovative volumetric DBS sampling device. Methods Clinical validation was performed by direct comparison of paired DBS and whole blood (WB) (tacrolimus) and plasma (mycophenolic acid) concentrations and AUCs. Agreement was evaluated using Passing-Bablok regression, Bland-Altman analysis and DBS-to-WB predictive performance. TDM dosing recommendations based on both methods were compared to assess clinical impact. Results Paired tacrolimus (n = 200) and mycophenolic acid (n = 192) DBS and WB samples were collected from 65 kidney(-pancreas) transplant recipients. Differences for tacrolimus and mycophenolic acid were within ±20% for 84.5% and 76.6% of concentrations and 90.5% and 90.7% of AUCs, respectively. Tacrolimus and mycophenolic acid dosing recommendation differences occurred on 44.4% and 4.7% of occasions. Tacrolimus DBS dosing recommendations were 0.35 ± 0.14 mg higher than for WB and 8 ± 3% of the initial dose. Mycophenolic acid DBS dosing recommendations were 23.3 ± 31.9 mg lower than for plasma and 2 ± 3.5% of the initial dose. Conclusions Tacrolimus and mycophenolic acid TDM for outpatient renal transplant recipients, based on abbreviated AUC collected with a DBS sampling device, is comparable to conventional TDM based on WB sampling. Patient training and guidance on good blood-spotting practices is essential to ensure method feasibility.

Introduction: Mitomycin C (MMC) is commonly used in patients with colorectal peritoneal metastases (CPM) treated with cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). MMC requires metabolic activation prior to exert its cytotoxic effect of which the main activating enzymes are NQO1 and POR. However, not all patients are able to activate MMC for example due to polymorphisms in the genes encoding these enzymes. The aim of this study was to investigate the association of NQO1*2, NQO1*3, and POR*28 with the efficacy of CRS + HIPEC with MMC in patients with CPM.Method: A retrospective follow-up design was used to study genetic association in patients with histologically proven CPM treated with CRS + HIPEC with MMC with respect to peritoneal recurrence rate after 3 months (primary endpoint), after 6 months, disease-free survival and overall survival. Genetic polymorphisms NQO1*2, NQO1*3, and POR*28 were tested for association.Results: A total of 253 patients were included. In NQO1*3 carriers the peritoneal recurrence rate 3 and 6 months after HIPEC was significantly higher than in wild type patients, respectively 30.0% vs 3.8% (p = 0.009) and 40.0% vs 12.1% (p = 0.031). In line with these results, NQO1*3 was associated with a shorter disease-free survival (HR 2.04, 95% CI [1.03-4.03]). There was no significant association with overall survival (HR 1.42, 95% CI [0.66-3.07]).Conclusion: Carriership of the NQO1*3 allele is associated with worse peritoneal recurrence rate and disease-free survival. These results suggest that individualization of patients treated with CRS + HIPEC based upon pharmacogenetics may be beneficial. (C) 2020 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Purpose Tamoxifen has a wide inter-variability. Recently, two SNPs in the 3′-untranslated region (UTR) of the SULT1A1 gene, rs6839 and rs1042157, have been associated with decreased SULT1A1 activity. The aim of this study is to investigate the role of the rs6839 and rs1042157 on tamoxifen metabolism and relapse-free survival (RFS) in women diagnosed with early-breast cancer receiving tamoxifen. Methods Samples from 667 patients collected in the CYPTAM study (NTR1509) were used for genotyping (CYP2D6, SULT1A1 rs6839 and rs1042157) and measurements of tamoxifen and metabolites. Patients were categorized in three groups depending on the decreased SULT1A1 activity due to rs6839 and rs1042157: low activity group (rs6839 (GG) and rs1042157 (TT)); high activity group (rs6839 (AA) and rs1042157 (CC)); and medium activity group (all the other combinations of rs6839 and rs1042157). Associations between SULT1A1 phenotypes and clinical outcome (RFS) were explored. Results In the low SULT1A1 activity group, higher endoxifen and 4-hydroxy-tamoxifen concentrations were found, compared to the medium and high activity group (endoxifen: 31.23 vs. 30.51 vs. 27.00, p value: 0.016; 4-hydroxy-tamoxifen: 5.55 vs. 5.27 vs. 4.94, p value:0.05). In terms of relapse, the low activity group had a borderline better outcome compared to the medium and high SULT1A1 activity group (adjusted Hazard ratio: 0.297; 95% CI 0.088–1.000; p value: 0.05). Conclusion Our results suggested that rs6839 and rs1042157 SNPs have a minor effect on the concentrations and metabolic ratios of tamoxifen and its metabolites, and RFS in women receiving adjuvant tamoxifen. Electronic supplementary material The online version of this article (10.1007/s10549-018-4923-7) contains supplementary material, which is available to authorized users.

Aim: To benchmark knowledge and attitude of pharmacy students toward pharmacogenetics (PGx) and PGx testing and compare the results with practicing colleagues. Methods: All pharmacy students in The Netherlands were invited to participate in a web-based survey consisting of 28 questions. Out of the 824 invited students, 148 individuals (18.0%) completed the questionnaire. All responders believed in the concept of PGx and had high expectations toward PGx. The majority (96.6%) had received some form of education on PGx, but only 12.8% felt adequately informed. Results: When compared with practicing pharmacists, differences were observed in the use of information and feeling qualified to recommend PGx testing. Conclusion: More education on PGx is required in the curriculum to fill the perceived knowledge gap among future pharmacists.

This study aimed to identify single-nucleotide polymorphisms (SNPs) that are associated with outcome to treatment with sunitinib in patients with advanced gastrointestinal stromal tumors (GIST). Forty-nine SNPS involved in the pharmacokinetic and pharmacodynamic pathway of sunitinib were associated with progression-free survival (PFS) and overall survival (OS) in 127 patients with advanced GIST who have been treated with sunitinib. PFS was significantly longer in carriers of the TT genotype in POR rs1056878 (hazards ratio (HR) 4.310, 95% confidence interval (CI): 1.457-12.746, P = 0.008). The presence of the T-allele in SLCO1B3 rs4149117 (HR 2.024, 95% CI: 1.013-4.044, P = 0.046), the CCC-CCC alleles in SLC22A5 haplotype (HR 2.603, 95% CI: 1.2165.573, P = 0.014), and the GC-GC alleles in the IL4 R haplotype (HR 7.131, 95% CI: 1.518-33.496, P = 0.013) were predictive for OS. This shows that polymorphisms in the pharmacokinetic and pharmacodynamic pathways of sunitinib are associated with survival in GIST. This may help to identify patients that benefit more from treatment with sunitinib.

The tyrosine kinase inhibitor sunitinib is used as first-line therapy in patients with metastasized renal cell carcinoma (mRCC), given in fixed-dose regimens despite its high variability in pharmacokinetics (PKs). Interindividual variability of drug exposure may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic/pharmacodynamic (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662, and the soluble vascular endothelial growth factor receptors sVEGFR-2 and sVEGFR-3, were measured in 26 patients with mRCC within the EuroTARGET project and 21 patients with metastasized colorectal cancer (mCRC) from the C-II-005 study. Based on these observations, PK/PD models with potential influence of genetic predictors were developed and linked to time-to-event (TTE) models. Baseline sVEGFR-2 levels were associated with clinical outcome in patients with mRCC, whereas active drug PKs seemed to be more predictive in patients with mCRC. The models provide the basis of PK/PD-guided strategies for the individualization of anti-angiogenic therapies.

Imatinib trough levels have been associated with its clinical effects. During chronic use of imatinib, CYP2C8 becomes an important metabolizing enzyme because of cytochrome P450 3A4 (CYP3A4) autoinhibition. Single nucleotide polymorphisms (SNPs) in CYP2C8 may affect imatinib trough levels. This study investigates the effect of common CYP2C8 polymorphisms [*1B (rs7909236), *1C (rs17110453), *3 (rs11572080 and rs10509681), and *4 (rs1058930)] on steady-state trough levels imatinib during chronic imatinib use in 43 patients with chronic myeloid leukemia or gastrointestinal stromal tumors. Standardized imatinib trough levels did not show a significant difference between wild-type and variant groups for any of the tested SNPs, but an association with age was found, with older patients having higher trough levels. This suggests that common CYP2C8 SNPs have no effect on the pharmacokinetics of imatinib.

The identification of biomarkers able to predict clinical benefit from vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors is urgently needed. Recently, Maitland and colleagues described an association between KDR-rs34231037 and soluble VEGFR2 levels as well as pazopanib pharmacodynamics. We investigated in a well-characterized series of metastatic clear cell renal cell carcinoma patients whether rs34231037 could influence sunitinib response. Clinical data and DNA were available from an international series of 276 patients. KDR-rs34231037 association with sunitinib response, clinical benefit, and progression-free survival was analyzed using logistic and Cox regression analyses. We found that G-allele carriers were over-represented among patients with clinical benefit during sunitinib treatment compared with those refractory to the treatment (odds ratio: 3.78; 95% confidence interval: 1.02-14.06; P=0.047, multivariable analysis). In conclusion, rs34231037 variant carriers seemed to have better sunitinib response than wild-type patients. Moreover, the association with tumor size reduction suggests that this single nucleotide polymorphism might also identify patients with successful tumor downsizing under anti-VEGFR therapy.

The clinical implementation of pharmacogenomics is becoming more common, in part due to the availability of clinical guidelines that describe how to use pharmacogenetics test results to optimize medication therapy. In this chapter, we discuss the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group guidelines, including the writing process, components and recommendations, the application of the guidelines to clinical practice, and guideline dissemination. Although these guidelines have facilitated the adoption of pharmacogenomics in clinical practice, education of providers and patients remains a challenge. Education must be delivered in scalable, sustainable, and updatable formats. This chapter describes provider education from an operational and clinical perspective and also highlights the importance of empowering patients through education.

3574 Background: Irinotecan is commonly used in the treatment of advanced colorectal and pancreatic cancer. The polymorphisms UGT1A1*28 (7 TA repeats) and UGT1A1*93 (SNP -3156G > A) are significantly associated with increased systemic exposure of irinotecan’s active metabolite SN-38 and subsequently severe irinotecan-associated adverse-events (AEs) including (febrile) neutropenia and diarrhea. Severe AEs may lead to hospitalization, loss of quality of life, treatment delay and/or treatment discontinuation. Nonetheless, prospective genetic screening is not yet routinely performed. The aim of this study was to determine the safety and pharmacokinetics of UGT1A1 genotype-guided dosing of irinotecan in UGT1A1 poor metabolizers (PMs), i.e. UGT1A1 *28/*28 and/or UGT1A1*93/*93 individuals, in order to reduce the incidence of severe irinotecan-associated AEs. Methods: A prospective, multi-center, non-randomized study was conducted in patients intended to be treated with irinotecan at a dose of ≥ 180 mg/m2 or 450-600 mg flat dose. All patients were pre-therapeutically genotyped for UGT1A1*28 and UGT1A1*93. In UGT1A1 PMs, an initial 30% dose reduction in the first cycle was applied followed by further individual dose titration based on neutrophil count and clinical tolerability. The primary endpoint was the incidence of febrile neutropenia in the first 2 cycles of irinotecan treatment. UGT1A1 PMs were compared to 1] historical control patients, i.e. homozygous polymorphic patients treated with full dose therapy identified from systematic literature review and to 2] UGT1A1 non-PMs treated with standard dose therapy. In addition, systemic SN-38 exposure (AUC0-500h) of reduced dosing in the UGT1A1 PM cohort was compared to a standard dosed irinotecan patient cohort [doi: 10.1200/JCO.2000.18.1.195] by an independent T-test. Results: A total of 349 patients were pre-therapeutically genotyped and included for analysis. Thirty-one (8.9%) patients were UGT1A1 PM, in whom an initial median 30% dose reduction was applied. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical controls (n = 50) (p = 0.042) and comparable with the incidence (4.1%; p = 0.632) in UGT1A1 non-PMs treated with full dose therapy. The systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs (n = 17) was comparable to the systemic exposure of the standard dosed irinotecan patient cohort (n = 46) with a relative difference of +24% (p = 0.054) with a geometric mean (CV) of SN-38 AUC0-500h of 391 (43.7%) versus 298 (75.3%) ng*h/mL, respectively. Conclusions: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan. In addition, systemic drug exposure remained adequate, despite the 30% dose reduction. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve the individual patient safety. Clinical trial information: Trial NL6270 (NTR6612).

Personalized medicine strives to optimize drug treatment for the individual patient by taking into account both genetic and non-genetic factors for drug response. Inflammation is one of the non-genetic factors that has been shown to greatly affect the metabolism of drugs—primarily through inhibition of cytochrome P450 (CYP450) drug-metabolizing enzymes—and hence contribute to the mismatch between the genotype predicted drug response and the actual phenotype, a phenomenon called phenoconversion. This review focuses on inflammation-induced drug metabolism alterations. In particular, we discuss the evidence assembled through human in-vitro models on the effect of inflammatory mediators on clinically relevant CYP450 isoform levels and their metabolizing capacity. We also present an overview of the current understanding of the mechanistic pathways via which inflammation in hepatocytes may modulate hepatic functions that are critical for drug metabolism. Furthermore, since large inter-individual variability in response to inflammation is observed in human in-vitro models and clinical studies, we evaluate the potential role of pharmacogenetic variability in the inflammatory signaling cascade and how this can modulate the outcome of inflammation on drug metabolism and response.

Background The insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth, proliferation and cell cycle progression and associated with tumor genesis and therapy resistance. This study aims to elucidate whether variation in the IGF-1 pathway is predictive for pathologic response in early breast cancer (BC) patients taking part in the phase III NEOZOTAC trial, randomizing between 6 cycles of neoadjuvant TAC chemotherapy with or without zoledronic acid. Method Formalin-fixed paraffin-embedded (FFPE) tissue samples of pre-chemotherapy biopsies and operation specimens were collected for analysis of IGF-1 receptor (IGF-1R) expression using IHC (n=216) and for analysis of 8 candidate SNPs in genes of the IGF-1 pathway (n=184) using OpenArray® RealTime PCR. Optionally, blood samples were collected immediately before chemotherapy for determination of glucose, insulin, IGF-1, IGF-2 and IGF-BP3. Associations with patient and tumor characteristics and chemotherapy response according to Miller and Payne (MP) pathologic response were performed using chi square and logistic regression analyses. Results High IGF-1R expression was associated with estrogen receptor expression (P=0.001). During chemotherapy, a significant number of the tumors (47.2%) showed a decrease in IGF-1R expression, while in a small number of the tumors an upregulation was seen (15.1%). IGF-1R expression before treatment was not associated with pathological response, however absence of IGF-1R expression after treatment was associated with a better response in multivariate analyses (P=0.012) and patients with a decrease in expression during treatment showed a better response to chemotherapy as well (P=0.008). Moreover, the variant T allele of 3129G>T in IGF-1R (rs2016347) was associated with a better pathological response in multivariate analyses (P=0.032). In addition, high glucose and insulin levels were associated with positive lymph node status before chemotherapy in multivariate analysis (P=0.019) and (P=0.031), respectively. Conclusion Neoadjuvant chemotherapy induced changes in the IGF-1R expression in most of the tumors. Absence or diminished expression of IGF-1R after treatment was associated with a better pathological response. Additionally, we found a SNP (rs2016347) in IGF-1R as a potential predictive marker for chemotherapy efficacy in BC patients treated with TAC. These findings may help to select patients who might benefit from (co-)treatment with an IGF-1 pathway inhibitor. Citation Format: de Groot S, Charehbili A, van Laarhoven HWM, Mooyaart AL, Dekker-Ensink NG, van de Ven S, Janssen LGM, Swen JJ, Smit VTHBM, Heijns JB, Kessels LW, van der Straaten RJHM, Bhringer S, Gelderblom AJ, van der Hoeven JJM, Guchelaar HJ, Pijl H, Kroep JR. Insulin-like growth factor 1 receptor expression and polymorphism are associated with response to neoadjuvant chemotherapy in breast cancer patients: Results from the NEOZOTAC trial (BOOG 2010-01). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-54.

Contains fulltext : 229533.pdf (Publisher’s version ) (Open Access) One application of personalized medicine is the tailoring of medication to the individual, so that the medication will have the highest chance of success. In order to individualize medication, one must have a complete inventory of all current pharmaceutical compounds (a detailed formulary) combined with pharmacogenetic datasets, the genetic makeup of the patient, their (medical) family history and other health-related data. For healthcare professionals to make the best use of this information, it must be visualized in a way that makes the most medically relevant data accessible for their decision-making. Similarly, to enable bioinformatics analysis of these data, it must be prepared and provided through an interface for controlled computational analysis. Due to the high degree of personal information gathered for such initiatives, privacy-sensitive implementation choices and ethical standards are paramount. The Personal Genetic Locker project provides an approach to enable the use of personal genomic data in primary care. In this paper, we provide a description of the Personal Genetic Locker project and show its utility through a use case based on open standards, which is illustrated by the 4MedBox system.

Tacrolimus-modified release formulations allow for once-daily dosing, and adherence is better compared to the twice-daily immediate release formulation. When patients are switched from one formulation to another, variable changes in drug concentrations are observed. Current data suggest that the changes in drug exposure are larger in patients who express the CYP3A5 enzyme (CYP3A5 *1/*3 or *1/*1) compared to nonexpressers (CYP3A5*3/*3). Possibly, these differences are due to the fact that in the upper region of the small intestine CYP3A activity is higher, and that this expression of CYP3A decreases towards the more distal parts of the gut. Modified release formulations may therefore be subject to a less presystemic metabolism. However, the full implications of pharmacogenetic variants affecting the expression and function of drug transporters in the gut wall and of enzymes involved in phase I and phase II metabolism on the different formulations are incompletely understood, and additional studies are required. Conclusions: In all patients in whom the formulation of tacrolimus is changed, drug levels need to be checked to avoid clinically relevant under- or overexposure. In patients with the CYP3A5 expresser genotype, this recommendation is even more important, as changes in drug exposure can be expected.

Currently, germline pharmacogenomics (PGx) is successfully implemented within certain specialties in clinical care. With the integration of PGx in pharmacotherapy multiple stakeholders are involved, which are identified in this chapter. Clinically relevant pharmacogenes with their related PGx test are discussed, along with diagnostic test criteria to guide clinicians and policy makers in PGx test selection. The chapter further reviews the similarities and the differences between the guidelines of the Dutch Pharmacogenetics Working Group and the Clinical Pharmacogenetics Implementation Consortium which both support healthcare professionals in understanding PGx test results and help guiding pharmacotherapy by providing evidence-based dosing recommendations. Finally, clinical studies which provide scientific evidence and information on cost-effectiveness supporting clinical implementation of PGx in clinical care are discussed along with the remaining barriers for adoption of PGx testing by healthcare professionals.

Currently, germline pharmacogenomics (PGx) is successfully implemented within certain specialties in clinical care. With the integration of PGx in pharmacotherapy multiple stakeholders are involved, which are identified in this chapter. Clinically relevant pharmacogenes with their related PGx test are discussed, along with diagnostic test criteria to guide clinicians and policy makers in PGx test selection. The chapter further reviews the similarities and the differences between the guidelines of the Dutch Pharmacogenetics Working Group and the Clinical Pharmacogenetics Implementation Consortium which both support healthcare professionals in understanding PGx test results and help guiding pharmacotherapy by providing evidence-based dosing recommendations. Finally, clinical studies which provide scientific evidence and information on cost-effectiveness supporting clinical implementation of PGx in clinical care are discussed along with the remaining barriers for adoption of PGx testing by healthcare professionals.

Aim: SNPs may be associated with (side) effects of chemotherapy and may be useful as biomarkers to predict febrile neutropenia. Patients & methods: 187 DNA samples extracted from formalin-fixed paraffin-embedded tissue from patients with stage II/III HER2-negative breast cancer were genotyped. Results: Candidate SNPs were selected and explored for association with febrile neutropenia and/or pathological complete response. TT genotype of 388C>T in FGFR4 (rs351855) had a tendency toward higher incidence of febrile neutropenia during neoadjuvant chemotherapy, compared with the CT (p = 0.383) genotype and compared with the CC genotype (p = 0.068). Conclusion: The TT genotype of 388C>T FGFR4 may be related to incidence of febrile neutropenia during neoadjuvant TAC (docetaxel, doxorubicin, cyclophosphamide) chemotherapy and is possibly useful as a patient-related risk factor when assessing febrile neutropenia risk. Original submitted 23 January 2015; Revision submitted 26 May 2015.

Tacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose-adjusted trough concentrations of tacrolimus as compared with those who are CYP3A5 nonexpressers (poor metabolizers), possibly delaying achievement of target blood concentrations. We summarize evidence from the published literature supporting this association and provide dosing recommendations for tacrolimus based on CYP3A5 genotype when known (updates at www.pharmgkb.org).

Background: In our exploratory studies, we associated single nucleotide polymorphisms (SNPs) in candidate genes with the efficacy and toxicities of sunitinib in metastatic renal cell carcinoma (mRCC). Objective: To see whether previously reported associations of SNPs with sunitinib-induced toxicities and efficacy in mRCC can be confirmed in a large cohort of patients. Design, setting, and participants: The mRCC patients treated with sunitinib and a DNA sample available were pooled from three exploratory studies conducted in the United States, Spain, and the Netherlands. A total of 22 SNPs and 6 haplotypes in 10 candidate genes related to the pharmacokinetics and pharmacodynamics of sunitinib were selected for association testing. Outcome measurements and statistical analysis: SNPs and haplotypes were tested for associations with toxicity, dose reductions, progression-free survival (PFS), overall survival (OS), and best objective response. Results and limitations: A total of 333 patients were included. We confirmed 2 of the 22 previously reported SNP associations. The presence of CYP3A5*1 was associated with dose reductions (odds ratio: 2.0; 95% confidence interval [CI], 1.0-4.0, p = 0.039). The presence of CGT in the ABCB1 haplotype was associated with an increased PFS (hazard ratio: 1.9; 95% CI, 1.3-2.6; p < 0.001) and remained significant after Bonferroni correction. These associations are consistent with prior observations. Conclusions: The confirmation of previously reported associations between polymorphisms in CYP3A5 and ABCB1 with sunitinib toxicity and efficacy, respectively, indicates that genotyping of these genetic variants will be useful for guiding sunitinib treatment. A prospective validation study is needed to confirm our findings on ABCB1 and CYP3A5 genetic polymorphisms. Patient summary: We confirmed that variants in genes involved in processing sunitinib through the body have an effect on sunitinib treatment outcome. These findings confirm the potential of testing for these genetic variants to improve individual patient care for patients with metastatic renal cell carcinoma treated with sunitinib. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Purpose Due to the diversity within Europe, the implementation of pharmacogenomic testing in clinical practice faces specific challenges. In the context of the European pharmacogenomics implementation project “Ubiquitous Pharmacogenomics” (U-PGx; funded by the European Commission), we studied the current educational background. Methods We developed a questionnaire including 29 questions. It was spread out to healthcare professionals working at the future implementation sites (in Austria, Greece, Italy, Netherlands, Slovenia, Spain and Great Britain) of the U-PGx project in preparation of an educational programme. Aim of the survey was to analyse the current educational situation at the implementation sites. Results In total, 70 healthcare professionals participated in the survey. Of participants, 84.3% found pharmacogenomics relevant to their current practice, but experience was still rare. More than two-thirds (65.7%) did not order nor recommend a pharmacogenomic test in the past year. This was mainly attributed to not having enough knowledge on pharmacogenomics (40.0%). Needs were identified in application of pharmacogenomics (identifying drugs 41.4%, interpreting test results 37.2%) as well as in underlining mechanisms (better knowledge on drug metabolism 67.1%, better knowledge on basic principles of pharmacogenomics 60.0%). Conclusions This study analysed the specific attitudes, experience and education on pharmacogenomics of future users. There was a general positive attitude and interest towards pharmacogenomic testing. However, the grade of own experience, and knowledge about application and interpretation of pharmacogenomics caused uncertainty. Thus, education and training programmes may be helpful for implementation of pharmacogenomics at a homogenous level within Europe. Electronic supplementary material The online version of this article (doi:10.1007/s00228-017-2292-5) contains supplementary material, which is available to authorized users.