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Fluoropyrimidines are chemotherapeutic agents widely used for the treatment of various solid tumors. Commonly prescribed FPs include 5-fluorouracil (5-FU) and its oral prodrugs capecitabine (CAP) and tegafur. Bioconversion of 5-FU prodrugs to 5-FU and subsequent metabolic activation of 5-FU are required for the formation of fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate, the active nucleotides through which 5-FU exerts its antimetabolite actions. A significant proportion of FP-treated patients develop severe or life-threatening, even fatal, toxicity. It is well known that FP-induced toxicity is governed by genetic factors, with dihydropyrimidine dehydrogenase (DPYD), the rate limiting enzyme in 5-FU catabolism, being currently the cornerstone of FP pharmacogenomics. DPYD-based dosing guidelines exist to guide FP chemotherapy suggesting significant dose reductions in DPYD defective patients. Accumulated evidence shows that additional variations in other genes implicated in FP pharmacokinetics and pharmacodynamics increase risk for FP toxicity, therefore taking into account more gene variations in FP dosing guidelines holds promise to improve FP pharmacotherapy. In this review we describe the current knowledge on pharmacogenomics of FP-related genes, beyond DPYD, focusing on FP toxicity risk and genetic effects on FP dose reductions. We propose that in the future, FP dosing guidelines may be expanded to include a broader ethnicity-based genetic panel as well as gene*gene and gender*gene interactions towards safer FP prescription.

Aim The COVID-19 pandemic caused by infection with the novel coronavirus SARS-CoV-2 is urging the scientific community worldwide to intense efforts for identifying and developing effective drugs and pharmacologic strategies to treat the disease. Many of the drugs that are currently in (pre)clinical development are addressing late symptoms of the disease. This review focuses on potential pharmacologic intervention at an early stage of infection which could result in less-infected individuals and less cases with severe COVID-19 disease due to reduced virus entry into the cells. Method We scanned the literature for evidence on drugs that target the virus entry machinery into host cells and consist mainly of ACE2 and TMPRSS2, as well as other cellular molecules regulating ACE2 expression, such as ADAM-17 and calmodulin. Results Several drugs/drug classes have been identified. Most of them are already used clinically for other indications. They include recombinant soluble ACE2, indirect ACE2 modulators (angiotensin receptor blockers, calmodulin antagonists, selective oestrogen receptor modifiers), TMPRSS2 inhibitors (camostat mesylate, nafamostat mesylate, antiandrogens, inhaled corticosteroids) and ADAM-17 enhancers (5-fluorouracil). Conclusion Several agents have potential for prophylactic and therapeutic intervention at the early stages of SARS-CoV-2 infection and COVID-19 disease and they should be urgently investigated further in appropriate preclinical models and clinical studies.

Introduction: Little is known about the overall quality of life (QOL) in patients newly diagnosed with venous thromboembolism (VTE) and atrial fibrillation (AF). We studied QOL in patients with VTE and AF immediately after the start of anticoagulant therapy, and after three months of treatment. Furthermore we identified whether QOL was affected by age, gender and nationality. Materials and Methods: The European pharmacogenetics of anticoagulant therapy (EU-PACT) study was a multicentre, randomized controlled trial of patients aged > 18 years diagnosed with VTE or AF. QOL was assessed using EuroQol 5 dimensions (EQ-5D) questionnaires. Results: The EQ-5D questionnaires were completed by 187 patients with VTE and 660 patients with AF. The QOL in patients diagnosed with VTE or AF was significantly impaired, however, during a 3 months treatment period, patients experienced an improvement (p < 0.05). The QOL in patients diagnosed with VTE improved with increasing age, with similar effects seen in men and women. Men and women diagnosed with AF differed in QOL (respectively 0.84 and 0.74, p < 0.05), and QOL decreased with age. Comparison between countries showed significant differences in the EQ-Index score at follow-up of patients with VTE, and in both EQ-Index score and EQ-VAS of patients with AF. Conclusions: The QOL in patients with VTE and AF is strongly reduced directly after the start of anticoagulant treatment, but improves within 3 months. Moreover, QOL is influenced by demographic and disease-specific variables. These findings provide useful information for future cost-effectiveness studies.

BACKGROUND: Age seemed to affect the interaction between coumarins and genotype in the acenocoumarol and phenprocoumon arm of the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial. OBJECTIVES: To investigate the effect of genotype-guided dosing stratified by age and the potential factors causing a difference. PATIENTS/METHODS: Data from the acenocoumarol/phenprocoumon arm of the EU-PACT trial was used. The percentage of time below, above and in the therapeutic range (TTR) during the initial 12 weeks of therapy were compared between the genotype-guided group and the control group among younger (

BACKGROUND: The multicenter, single-blind, randomized EU-PACT trial compared safety and efficacy of genotype-guided and non-genetic dosing algorithms for acenocoumarol and phenprocoumon in patients with atrial fibrillation or deep venous thrombosis. The trial showed no differences in the primary outcome between the two dosing strategies. OBJECTIVES: To explore possible reasons for the lack of differences between trial arms this secondary analysis of EU-PACT data evaluated the performance of both dosing algorithms across VKORC1-CYP2C9 genetic sub-groups. PATIENTS/METHODS: Anticoagulation control measured by international normalized ratio (INR) below (INR3) the therapeutic range was compared across VKORC1-CYP2C9 sub-groups. Due to a low number of patients per sub-group, trials for acenocoumarol and phenprocoumon were combined for analysis. RESULTS: Four weeks after therapy initiation genotype-guided dosing increased the mean percentage of time in therapeutic INR range (PTIR) in the VKORC1 GG-CYP2C9 *1*1 sub-group as compared to the non-genetic dosing (%-point difference 14.68, 95% CI [5.38; 23.98]). For the VKORC1 AA-CYP2C9 *1*1 sub-group, there was a higher risk of under-anticoagulation with the genotype-guided algorithm (19.9%-points; 95% CI, 11.6 to 28.2). Twelve weeks after therapy initiation no statistically significant differences in anticoagulation control between trial arms were noted across the VKORC1-CYP2C9 genetic sub-groups. CONCLUSIONS: EU-PACT genetic-guided dose initiation algorithms for acenocoumarol and phenprocoumon could have predicted the dose extra cautiously in the VKORC1 AA-CYP2C9 *1*1 sub-group. Adjustment of the genotype-guided algorithm could lead to a higher benefit of genotyping. This article is protected by copyright. All rights reserved.

Variability in vitamin K antagonist (VKA) dosing is partially explained by genetic polymorphisms. We performed a meta-analysis to determine whether genotype-guided VKA dosing algorithms decrease a composite of death, thromboembolic events and major bleeding (primary outcome) and improve time in therapeutic range (TTR). We searched MEDLINE, EMBASE, CENTRAL, trial registries and conference proceedings for randomised trials comparing genotype-guided and standard (non genotype-guided) VKA dosing algorithms in adults initiating anticoagulation. Data were pooled using a random effects model. Of the 12 included studies (3,217 patients), six reported all components of the primary outcome of mortality, thromboembolic events and major bleeding (2,223 patients, 87 events). Our metaanalysis found no significant difference between groups for the primary outcome (relative risk 0.85, 95 % confidence interval [CI] 0.54-1.34; heterogeneity X2=4.46, p=0.35, I2=10 %). Based on 10 studies (2,767 patients), TTR was significantly higher in the genotypeguided group (mean difference (MD) 4.31 %; 95 % CI 0.35, 8.26; heterogeneity _2=43.31, p

Background It has not been investigated how much the use of clinical factors in a dosing algorithm improves the percentage of time in therapeutic range (TTR). The present study aimed to compare the effect of dosing algorithms for acenocoumarol and phenprocoumon including clinical patient characteristics with standard care in the Netherlands. Setting: The pre-EU-PACT study, an observational study in the Netherlands, was used to obtain standard care data. Data from the Dutch patients in the EU-PACT trial (comparing the use of a clinical algorithm with and without genetic information) was used for the clinical dosing algorithm. Methods For both acenocoumarol and phenprocoumon, the percentage of time in, below and above therapeutic International Normalized Ratio (INR) range during 12 weeks after treatment initiation were assessed in both studies. Results During the weeks 2-12, the clinical dosing algorithm of acenocoumarol (80 patients) led to a higher TTR (74.3% versus 68.0% in range 2.0-3.5, 95% Confidence interval [CI] difference: 0.5% to 11.8%), and a reduced percentage of time below INR 2 and above INR 3.5, compared with standard care (272 patients). For phenprocoumon, compared with standard care (484 patients), 80 patients treated by the dosing algorithm did not obtained a significantly higher TTR in range 2.0-3.5 or a lower percentage of time above 3.5, however, they spent more time with INR below 2. Conclusion The use of a clinical dosing algorithm for acenocoumarol seemed to improve the quality of anticoagulation therapy during the treatment of initial 2-12 weeks. For phenprocoumon, there was no statistically difference in anticoagulation control.

Background It has not been investigated how much the use of clinical factors in a dosing algorithm improves the percentage of time in therapeutic range (TTR). The present study aimed to compare the effect of dosing algorithms for acenocoumarol and phenprocoumon including clinical patient characteristics with standard care in the Netherlands. Setting: The pre-EU-PACT study, an observational study in the Netherlands, was used to obtain standard care data. Data from the Dutch patients in the EU-PACT trial (comparing the use of a clinical algorithm with and without genetic information) was used for the clinical dosing algorithm. Methods For both acenocoumarol and phenprocoumon, the percentage of time in, below and above therapeutic International Normalized Ratio (INR) range during 12 weeks after treatment initiation were assessed in both studies. Results During the weeks 2-12, the clinical dosing algorithm of acenocoumarol (80 patients) led to a higher TTR (74.3% versus 68.0% in range 2.0-3.5, 95% Confidence interval [CI] difference: 0.5% to 11.8%), and a reduced percentage of time below INR 2 and above INR 3.5, compared with standard care (272 patients). For phenprocoumon, compared with standard care (484 patients), 80 patients treated by the dosing algorithm did not obtained a significantly higher TTR in range 2.0-3.5 or a lower percentage of time above 3.5, however, they spent more time with INR below 2. Conclusion The use of a clinical dosing algorithm for acenocoumarol seemed to improve the quality of anticoagulation therapy during the treatment of initial 2-12 weeks. For phenprocoumon, there was no statistically difference in anticoagulation control.

Aim: The need for pharmacogenomic education is becoming more and more urgent. Our aim was to evaluate the progress in pharmacogenomics education since then, and to put forward further recommendations. Methods: A survey was sent to 248 schools of medicine, pharmacy, nursing and health professions around the world. Results: The majority of the study programs (87%) include pharmacogenomics education, which is generally taught as part of the pharmacology curriculum. On average, educators and teachers have selected appropriate and highly relevant pharmacogenomics biomarkers to include in their teaching programs. Conclusions: Based on the results, we can conclude that the state of pharmacogenomics education at the surveyed universities has improved substantially since 2005. ispartof: PHARMACOGENOMICS vol:20 issue:9 pages:643-657 ispartof: location:England status: published