A5016551871- Pharmacogenetics and Drug Metabolism
- Genomics and Rare Diseases
- Pharmaceutical studies and practices
- Statistical Methods in Clinical Trials
- Drug Transport and Resistance Mechanisms
- Analytical Chemistry and Chromatography
- Computational Drug Discovery Methods
- Biochemical and Molecular Research
- Inflammatory mediators and NSAID effects
- Cancer therapeutics and mechanisms
- Glycosylation and Glycoproteins Research
- Renal Transplantation Outcomes and Treatments
- Childhood Cancer Survivors' Quality of Life
- Dermatology and Skin Diseases
- Allergic Rhinitis and Sensitization
- Genetic Neurodegenerative Diseases
- Tracheal and airway disorders
- Pharmacological Effects and Toxicity Studies
- Acute Lymphoblastic Leukemia research
- Respiratory viral infections research
- Analytical Methods in Pharmaceuticals
- Hormonal Regulation and Hypertension
- HIV/AIDS drug development and treatment
- 14-3-3 protein interactions
- Asthma and respiratory diseases
Leiden University Medical Center
2019-2025
Center for Personalized Cancer Treatment
2020
University Medical Center Utrecht
2018
Utrecht University
2013-2018
A neural network model trained on full CYP2D6 gene sequences increases the ability to predict CYP2D6-mediated tamoxifen metabolism.
Abstract The immunosuppressant and narrow therapeutic index drug tacrolimus is metabolized mainly via cytochrome P450 (CYP) 3A4 CYP3A5. For its pharmacokinetics (PK), high inter‐ intra‐individual variability can be observed. Underlying causes include the effect of food intake on absorption as well genetic polymorphism in CYP3A5 gene. Furthermore, highly susceptible to drug–drug interactions, acting a victim when coadministered with CYP3A perpetrators. This work describes development...
Background: Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections (LRTI) during first year life. Antibiotic treatment recommended in cases suspected bacterial coinfection. The aim this prospective study was to estimate incidence coinfections and amount antibiotic overuse children infected with RSV using expert panel diagnosis. Methods: Children 1 month age over LRTI or fever without source were prospectively recruited hospitals Netherlands Israel....
For ~ 80 drugs, widely recognized pharmacogenetics dosing guidelines are available. However, the use of these in clinical practice remains limited as only a fraction patients is subjected to pharmacogenetic screening. We investigated feasibility repurposing whole exome sequencing (WES) data for panel 42 variants 11 pharmacogenes provide pharmacogenomic profile. Existing diagnostic WES‐data from child‐parent trios totaling 1,583 individuals were used. Results successfully extracted 39...
The use of pharmacogenomics in clinical practice is becoming standard care. However, due to the complex genetic makeup pharmacogenes, not all variation currently accounted for. Here, we show utility long-read sequencing resolve pharmacogenes by analyzing a well-characterised sample. This data consists long reads that were processed phased haploblocks. 73% fully covered one haploblock, including 9/15 genes are 100% complex. Variant calling accuracy was high, with 99.8% recall and precision...
The antiarrhythmic agent quinidine is a potent inhibitor of cytochrome P450 (CYP) 2D6 and P-glycoprotein (P-gp) therefore recommended for use in clinical drug-drug interaction (DDI) studies. However, as also substrate CYP3A4 P-gp, it susceptible to DDIs involving these proteins. Physiologically-based pharmacokinetic (PBPK) modeling can help mechanistically assess the absorption, distribution, metabolism, excretion processes drug has proven its usefulness predicting even complex scenarios....
The polymorphic CYP2D6 enzyme plays a pivotal role in the metabolism of approximately 25% clinically prescribed drugs. However, impact specific genetic variants on interindividual variability CYP2D6‐mediated drug remains insufficiently quantified. This translational study sought to address this gap by analyzing genotypes and phenotypes patients two large clinical cohorts, focusing substrates risperidone desmethyltamoxifen. analysis incorporated novel haplotypes substrate‐specific differences...
Background: Inter-individual differences in drug response based on genetic variations can lead to toxicity and treatment inefficacy. A large part of this variability is caused by variants pharmacogenes. Unfortunately, the Single Nucleotide Variant arrays currently used clinical pharmacogenomic (PGx) testing are unable detect all these genes. Long-read sequencing, other hand, has been shown be able resolve complex (pharmaco) In study we aimed assess value long-read sequencing for research PGx...
CYP3A4 activity shows considerable interindividual variability. Although studies indicate 60%-80% is heritable, common single nucleotide variants (SNVs) in together only explain ~10%. Transcriptional factors, such as the testis-specific Y-encoded-like proteins (TSPYLs) family, have been reported to regulate expression of CYP enzymes including vitro. Here, we investigated effect genetic TSPYL on using data from a clinical study and human liver bank. Five SNVs (rs3828743, rs10223646,...
Abstract Background The Alpe-DPD study (NCT02324452) demonstrated that prospective genotyping and dose-individualization using four alleles in DPYD ( *2A/rs3918290, c.1236G > A/rs75017182, c.2846A T/rs67376798 c.1679 T G/rs56038477) can mitigate the risk of severe fluoropyrimidine toxicity. However, this could not prevent all toxicities. goal was to identify additional genetic variants, both inside outside , may contribute Methods Biospecimens data from were used. Exon sequencing...
Conducting clinical studies on drug–drug‐gene interactions (DDGIs) and extrapolating the findings into dose recommendations is challenging due to high complexity of these interactions. Here, physiologically‐based pharmacokinetic (PBPK) modeling networks present a new avenue for exploring such complex scenarios, potentially informing guidelines handling patient‐specific DDGIs at bedside. Moreover, they provide an established framework drug–drug interaction (DDI) submissions regulatory...
In pediatric oncology, pharmacogenetic guidelines are underutilized and the potential impact of pre‐emptive screening remains largely unexplored despite this field's need for individualized approaches. While comprehensive not yet available all anticancer drugs, evidence‐based recommendations exist a subset supportive care drugs including thiopurines, irinotecan, capecitabine, 5‐fluorouracil. study, we evaluate by retrospectively identifying opportunities dose or treatment adjustments within...
Genetic variation in the gene encoding CYP2D6 is used to guide drug prescribing clinical practice. However, genetic variants show substrate-specific effects that are currently not accounted for. With a systematic literature, we retrieved 22 original studies describing vitro experiments focusing on alleles (CYP2D6*1, *2, *10 and *17) substrates. Allele activity (clearance of allele interest divided by clearance wildtype) was extracted. The results support hypothesis existence substrate...
Pharmacogenomics is a key component of personalized medicine. It promises safer and more effective drug treatment by individualizing the choice dose based on an individual’s genetic profile 1,2 . The majority commonly prescribed drugs are metabolized small set Cytochrome P450 (CYP) enzymes 3 In clinical practice, biomarkers being used to categorize patients into predefined *-alleles predict CYP450 enzyme activity adjust dosages accordingly. Yet, this approach has important limitations as it...
Abstract 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 analyzed through deep filtration separately. Theoretical drug induced phenoconversion was assessed the patients, using sequence2script . In total, 4539 rare variants (including 115 damaging non-synonymous) identified. Four...
Huntington's disease (HD) is a hereditary, neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. Currently, HD can only be managed symptomatically, including large variety of prescribed drugs. Many patients experience negative medication effects (e.g. side or non-response). Pharmacogenetic (PGx) studies show how genetic variation affects both efficacy toxicity holds the potential to improve these outcomes drug treatment.To classify effect PGx profile CYP2C19...
Paediatric oncology patients who develop severe chemotherapy-induced toxicity that requires dose reduction, delay or termination of treatment are at risk decreased efficacy. Previous research has provided evidence genetic variants in TPMT, NUDT15, UGT1A1 and DPYD associated with anticancer drugs. This led to pharmacogenetic guidelines integrated into clinical practice paediatric oncology. Recently, novel have been a higher developing toxicity. In this case series, we selected 21 genotyped...
Atopic dermatitis (AD) and asthma often coexist. Both diseases can have a major impact on the lives of children with AD their caregivers. To investigate association patient characteristics, comorbidities who both AD. Children (n = 140) were selected from larger cohort reported use medication. The Children's Dermatology Life Quality Index (CDLQI) was used to assess (QoL), Self‐Assessed Eczema Area Severity (SA‐EASI) measure severity. Characteristics assessed included: age, sex, number type...
Abstract Objectives To study topical corticosteroid use in Dutch asthmatic children using pharmacy dispensing data and to assess whether physicians prescribe corticosteroids this population according clinical guidelines. Methods Medication histories of asthma medication were extracted from the system 100 community pharmacies. The incidence rate potency prescriptions per age assessed. rates different groups compared Pearson chi‐square test. Generalized linear models used prescription behavior...
Abstract Pharmacogenomics (PGx)-guided drug treatment is one of the cornerstones personalized medicine. However, genes involved in response are highly complex and known to carry many (rare) variants. Current technologies (short-read sequencing SNP panels) limited their ability resolve these characterize all Moreover, cannot always phase variants allele origin. Recent advance long-read have shown promise resolving problems. Here we present a panel-based approach for PGx using PacBio HiFi...