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Journal of Child and Adolescent... Feb 2024Oxcarbazepine is thought to be better-tolerated and less susceptible to drug-drug interactions than its predecessor, carbamazepine. Genetic testing for *15:02 is... (Review)
Review
Oxcarbazepine is thought to be better-tolerated and less susceptible to drug-drug interactions than its predecessor, carbamazepine. Genetic testing for *15:02 is recommended in specific populations to identify those at high risk of severe hypersensitivity reactions; however, other pharmacologic and pharmacogenetic factors that can impact drug disposition may be involved. We present a case of an 8-year-old boy treated with oxcarbazepine who developed drug reaction with eosinophilia and systemic symptoms (DRESS) with Stevens-Johnsons syndrome overlap and was negative for *15:02. We review the extant literature related to oxcarbazepine disposition, and potential pharmacogenetic variants in aldoketoreductase 1C ()2-4 that may contribute to this risk. Genetic variability in oxcarbazepine disposition pathways may contribute to tolerability and toxicity, including the development of hypersensitivity reactions. While preemptive genetic testing for *15:02 in individuals of Asian ancestry is recommended to prevent severe hypersensitivity reactions to oxcarbazepine, oxcarbazepine concentrations and variation may contribute to the risk of severe adverse reactions. We provide recommendations for future study to elucidate whether these individual factors are important for reducing the risk of severe adverse events.
Topics: Male; Child; Adolescent; Humans; Oxcarbazepine; Anticonvulsants; Pharmacogenetics; HLA-B Antigens; Stevens-Johnson Syndrome
PubMed: 38377523
DOI: 10.1089/cap.2023.0064 -
Pharmaceutics Oct 2023The modalities for prescribing a psychotropic (dose and choice of molecule) are currently unsatisfactory, which can lead to a lack of efficacy of the treatment... (Review)
Review
The modalities for prescribing a psychotropic (dose and choice of molecule) are currently unsatisfactory, which can lead to a lack of efficacy of the treatment associated with prolonged exposure of the patient to the symptoms of his or her illness and the side effects of the molecule. In order to improve the quality of treatment prescription, a part of the current biomedical research is dedicated to the development of pharmacogenetic tools for individualized prescription. In this guideline, we will present the genes of interest with level 1 clinical recommendations according to PharmGKB for the two major families of psychotropics: antipsychotics and antidepressants. For antipsychotics, there are and , and for antidepressants, , , and . The study will focus on describing the role of each gene, presenting the variants that cause functional changes, and discussing the implications for prescriptions in clinical practice.
PubMed: 38004520
DOI: 10.3390/pharmaceutics15112540 -
Molecular Genetics and Genomics : MGG Jul 2023Diabetes is known to increase susceptibility to hypertension due to increase in inflammation, oxidative stress, and endothelial dysfunction, leading to vascular... (Review)
Review
Diabetes is known to increase susceptibility to hypertension due to increase in inflammation, oxidative stress, and endothelial dysfunction, leading to vascular stiffness. The polytherapy might lead to several drug-drug interactions (DDIs), which cause certain life-threatening complications such as diabetic nephropathy and hypoglycaemia. So, in this review we focused on drug-drug interactions and impact of genetic factors on drug responses for better disease management. Drug-drug interactions (DDIs) may act either synergistically or antagonistically. For instance, a combination of metformin with angiotensin II receptor antagonist or angiotensin-converting enzyme inhibitors (ACEIs) synergistically improves glucose absorption, whereas the same hypertensive drug combination with sulphonylurea might cause severe hypoglycaemia sometimes. Thiazolidinediones (TDZs) can cause fluid retention and heart failure when taken alone, but a combination of angiotensin II receptor antagonist with TZDs prevents these side effects. Interindividual genetic variation affects the DDI response. We found two prominent genes, GLUT4 and PPAR-γ, which are common targets for most of the drug. So, all of these findings established a connection between drug-drug interaction and genetics, which might be used for effective disease management.
Topics: Humans; Pharmacogenetics; Diabetes Mellitus; Hypertension; Angiotensin Receptor Antagonists; Hypoglycemia
PubMed: 37149837
DOI: 10.1007/s00438-023-02011-7 -
Expert Opinion on Drug Metabolism &... 2023
Topics: Humans; Pharmacogenetics; Tyrosine Kinase Inhibitors; Precision Medicine
PubMed: 37916644
DOI: 10.1080/17425255.2023.2277758 -
Animal Genetics Feb 2024The recent advances in high-throughput next-generation sequencing technologies have heralded the arrival of the Big Data era. As a result, the use of pharmacogenetics in... (Review)
Review
The recent advances in high-throughput next-generation sequencing technologies have heralded the arrival of the Big Data era. As a result, the use of pharmacogenetics in drug discovery and individualized drug therapy has transformed the field of precision medicine. This paradigm shift in drug development programs has effectively reshaped the old drug development practices, which were primarily concerned with the physiological status of patients for drug development. Pharmacogenomics bridges the gap between pharmacodynamics and pharmacokinetics, advancing current diagnostic and treatment strategies and enabling personalized and targeted drug therapy. The primary goals of pharmacogenetic studies are to improve drug efficacy and minimize toxicities, to identify novel drug targets, to estimate drug dosage for personalized medicine, and to incorporate it as a routine diagnostic for disease susceptibility. Although pharmacogenetics has numerous applications in individualized drug therapy and drug development, it is in its infancy in veterinary medicine. The objective of this review is to present an overview of historical landmarks, current developments in various animal species, challenges and future perspectives of genomics in drug development and dosage optimization for individualized medicine in veterinary subjects.
Topics: Animals; Pharmacogenetics; Precision Medicine; Genomics; High-Throughput Nucleotide Sequencing
PubMed: 37990577
DOI: 10.1111/age.13376 -
Pharmacological Research Apr 2024Here we present an account on the history of pharmacology in Spain. Pharmacology as an independent science in Europe began with the creation of university chairs. Of...
Here we present an account on the history of pharmacology in Spain. Pharmacology as an independent science in Europe began with the creation of university chairs. Of particular relevance was the appointment in 1872 of Osswald Shmiedeberg as chairman of an Institute of Pharmacology at the University of Strassbourg, Germany. Teófilo Hernando pioneered in Spain the new emerging pharmacology at the beginning of the XX Century. He made a posdoctoral stay in the laboratory of Schmiedeberg, working on digitalis. In 1912 he won the chair of "Materia Médica y Arte de Recetar" at "Universidad Central of Madrid" (today, "Universidad Complutense de Madrid", UCM). He soon decided to transform such subject to the emerging modern pharmacology, with the teaching of experimental pharmacology in the third course of medical studies and clinical therapeutics (today clinical pharmacology) in the sixth course. This was the status of pharmacology in 1920, supporting the view that Hernando was a pioneer of clinical pharmacology. However, the Spanish Civil War and the II Word War interropted this division of preclinical and clinical pharmacology; only in the 1980's was clinical pharmacolgy partially developed in Spain. From a scientific point of view, Hernando directly trained various young pharmacologists that extended the new science to various Spanish universities. Some of his direct disciples were Benigno Lorenzo Velázquez, Francisco García Valdecasas, Rafael Méndez, Tomás Alday, Gabriel Sánchez de la Cuesta, Dámaso Gutiérrez or Ramón P é rez-Cirera. One of the central research subject was the analysis of the effects of digitalis on the cat and frog heart. In the initiation of the 1970 s pharmacologists trained by those Hernando's students grew throughout various universities and the "Consejo Superior de Investigaciones Científicas" (CSIC). And hence, in 1972 the "Sociedad Española de Farmacología" (SEF) emerged. Later on, in the 1990's the "Sociedad Española de Farmacología Clínica (SEFC) also emerged. The relationship between the two societies is still weak. Out of the vast scope of the pharmacological sciences, Spanish pharmacologists have made relevant contributions in two areas namely, neuropsychopharmacology and cardiovacular pharmacology. Nonetheless, in other areas such as smooth muscle, gastroenterology, pharmacogenetics and hepatic toxicity, Spanish pharmacologists have also made relevant contributions. A succint description of such contributions is made. Finally, some hints on perspectives for the further development of preclinical and clinical pharmacology in Spain, are offered.
Topics: Humans; Spain; Europe; Pharmacology, Clinical; Pharmacogenetics; Pharmacology
PubMed: 38364957
DOI: 10.1016/j.phrs.2024.107104 -
Cancer Chemotherapy and Pharmacology Nov 2023Imatinib is presently the first-line choice for the treatment of chronic myeloid leukemia. However, there are limited real-world data on Chinese patients to support...
BACKGROUND
Imatinib is presently the first-line choice for the treatment of chronic myeloid leukemia. However, there are limited real-world data on Chinese patients to support individualized medicine. This work aims to characterize population pharmacokinetics in Chinese patients with chronic myeloid leukemia, investigate the effects of several covariates on imatinib exposure, and provide support for personalized medicine and dose reduction.
METHODS
A total of 230 patients with chronic myeloid leukemia were enrolled, and 424 steady-state concentration measurements were taken to perform the population pharmacokinetic analysis and Monte Carlo simulations with Phoenix NLME software. The effects of the demographic, biological, and pharmacogenetic (ten SNP corresponding to CYP3A4, CYP3A5, ABCB1, ABCG2, SCL22A1 and POR) covariates on clearance were evaluated.
RESULTS
A one-compartmental model best-described imatinib pharmacokinetics. The hemoglobin and the estimated glomerular filtration rate (< 85 mL⋅min⋅1.73 m) were associated with imatinib clearance. The genetic polymorphisms related to pharmacokinetics were not found to have a significant effect on the clearance of imatinib. The final model estimates of parameters are: k (h) = 0.329; V/F (L) = 270; CL/F (L⋅h) = 7.60.
CONCLUSIONS
Key covariates in the study population accounting for variability in imatinib exposure are hemoglobin and the estimated glomerular filtration rate. There is some need for caution when treating patients with moderate-to-severe renal impairment and significant hemoglobin changes.
Topics: Humans; Imatinib Mesylate; East Asian People; Pharmacogenetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid
PubMed: 37624393
DOI: 10.1007/s00280-023-04581-0 -
Frontiers in Oncology 2023Next-generation sequencing (NGS), including whole genome sequencing (WGS) and whole exome sequencing (WES), is increasingly being used for clinic care. While NGS data...
BACKGROUND
Next-generation sequencing (NGS), including whole genome sequencing (WGS) and whole exome sequencing (WES), is increasingly being used for clinic care. While NGS data have the potential to be repurposed to support clinical pharmacogenomics (PGx), current computational approaches have not been widely validated using clinical data. In this study, we assessed the accuracy of the Aldy computational method to extract PGx genotypes from WGS and WES data for 14 and 13 major pharmacogenes, respectively.
METHODS
Germline DNA was isolated from whole blood samples collected for 264 patients seen at our institutional molecular solid tumor board. DNA was used for panel-based genotyping within our institutional Clinical Laboratory Improvement Amendments- (CLIA-) certified PGx laboratory. DNA was also sent to other CLIA-certified commercial laboratories for clinical WGS or WES. Aldy v3.3 and v4.4 were used to extract PGx genotypes from these NGS data, and results were compared to the panel-based genotyping reference standard that contained 45 star allele-defining variants within , , , , , , , , , , , , , and .
RESULTS
Mean WGS read depth was >30x for all variant regions except for (average read depth was 29 reads), and mean WES read depth was >30x for all variant regions. For 94 patients with WGS, Aldy v3.3 diplotype calls were concordant with those from the genotyping reference standard in 99.5% of cases when excluding diplotypes with additional major star alleles not tested by targeted genotyping, ambiguous phasing, and hybrid alleles. Aldy v3.3 identified 15 additional clinically actionable star alleles not covered by genotyping within , , , , and . Within the WGS cohort, Aldy v4.4 diplotype calls were concordant with those from genotyping in 99.7% of cases. When excluding patients with copy number variation, all Aldy v4.4 diplotype calls except for one diplotype call were concordant with genotyping for 161 patients in the WES cohort.
CONCLUSION
Aldy v3.3 and v4.4 called diplotypes for major pharmacogenes from clinical WES and WGS data with >99% accuracy. These findings support the use of Aldy to repurpose clinical NGS data to inform clinical PGx.
PubMed: 37469403
DOI: 10.3389/fonc.2023.1199741 -
Farmacia Hospitalaria : Organo Oficial... Jun 2024Pharmacogenetics evaluates how genetic variations influence drug responses. Nowadays, genetic tests have advanced, becoming more affordable, and its integration is... (Review)
Review
INTRODUCTION
Pharmacogenetics evaluates how genetic variations influence drug responses. Nowadays, genetic tests have advanced, becoming more affordable, and its integration is supported by stronger clinical evidence. Guidelines such as those from CPIC (Clinical Pharmacogenetics Implementation Consortium) and resources like PharmGKB facilitate genotype-based prescribing; and organizations like the FDA promote genetic testing before initiating certain medications. Preventive pharmacogenetic panels seem promising, but further research on biomarkers and diverse populations is needed. The aim of this review is to analyze recent evidence on the genotype-drug response relationship to examine how the genetic profile of patients influences the clinical response to treatments, and analyze the areas of research that need further study to advance towards a genetic-based precision medicine.
MATERIALS AND METHODS
A systematic search was conducted on PubMed to identify articles investigating the genotype-drug response relationship. The search strategy included terms such as "pharmacogenetics", "personalized treatment", "precision medicine", "dose adjustment", "individualized dosing", "clinical routine" and "clinical practice." Clinical trials, observational studies, and meta-analyses published in English or Spanish between 2013 and 2023 were included. The initial search resulted in a total of 136 articles for analysis.
RESULTS
49 articles were included for the final analysis following review by two investigators. A relationship between genetic polymorphisms and drug response or toxicity was found for drugs such as opioids, GLP-1 agonists, tacrolimus, oral anticoagulants, antineoplastics, atypical antipsychotics, efavirenz, clopidogrel, lamotrigine, anti-TNF-α agents, voriconazole, antidepressants, or statins. However, for drugs like metformin, quetiapine, irinotecan, bisoprolol, and anti-VEGF agents, no statistically significant association between genotype and response was found.
CONCLUSION
The studies analyzed in this review suggest a strong correlation between genetic variability and individual drug responses, supporting the use of pharmacogenetics for treatment optimization. However, for certain drugs like metformin or quetiapine, the influence of genotype on their response remains unclear. More studies with larger sample sizes, greater ethnic diversity, and consideration of non-genetic factors are needed. The lack of standardization in analysis methods and accessibility to genetic testing are significant challenges in this field. As a conclusion, pharmacogenetics shows immense potential in personalized medicine, but further research is required.
PubMed: 38851909
DOI: 10.1016/j.farma.2024.03.010 -
Genes Sep 2023Health equity means the opportunity for all people and populations to attain optimal health, and it requires intentional efforts to promote fairness in patient...
Health equity means the opportunity for all people and populations to attain optimal health, and it requires intentional efforts to promote fairness in patient treatments and outcomes. Pharmacogenomic variants are genetic differences associated with how patients respond to medications, and their presence can inform treatment decisions. In this perspective, we contend that the study of pharmacogenomic variation within and between human populations-population pharmacogenomics-can and should be leveraged in support of health equity. The key observation in support of this contention is that racial and ethnic groups exhibit pronounced differences in the frequencies of numerous pharmacogenomic variants, with direct implications for clinical practice. The use of race and ethnicity to stratify pharmacogenomic risk provides a means to avoid potential harm caused by biases introduced when treatment regimens do not consider genetic differences between population groups, particularly when majority group genetic profiles are assumed to hold for minority groups. We focus on the mitigation of adverse drug reactions as an area where population pharmacogenomics can have a direct and immediate impact on public health.
Topics: Humans; Pharmacogenetics; Health Equity; Ethnicity; Pharmacogenomic Variants; Minority Groups
PubMed: 37895188
DOI: 10.3390/genes14101840