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International Journal of Molecular... Oct 2021Pharmacogenomic studies in epilepsy are justified by the high prevalence rate of this disease and the high cost of its treatment, frequent drug resistance, different... (Review)
Review
Pharmacogenomic studies in epilepsy are justified by the high prevalence rate of this disease and the high cost of its treatment, frequent drug resistance, different response to the drug, the possibility of using reliable methods to assess the control of seizures and side effects of antiepileptic drugs. Candidate genes encode proteins involved in pharmacokinetic processes (drug transporters, metabolizing enzymes), pharmacodynamic processes (receptors, ion channels, enzymes, regulatory proteins, secondary messengers) and drug hypersensitivity (immune factors). This article provides an overview of the literature on the influence of genetic factors on treatment in epilepsy.
Topics: ATP Binding Cassette Transporter, Subfamily B; Animals; Drug Resistance; Epilepsy; Humans; Inactivation, Metabolic; Pharmacogenomic Testing; Pharmacogenomic Variants
PubMed: 34769124
DOI: 10.3390/ijms222111696 -
Clinical and Experimental Rheumatology 2021Rheumatology medications are often associated with adverse drug reactions (ADRs) or inadequate response (IR). Pharmacogenomics may be a solution, but there is limited...
OBJECTIVES
Rheumatology medications are often associated with adverse drug reactions (ADRs) or inadequate response (IR). Pharmacogenomics may be a solution, but there is limited knowledge of its potential utility within rheumatology.
METHODS
We analysed medication changes and pharmacogenomically actionable prescriptions for all adult rheumatology outpatient encounters at our medical centre between 10/2012-12/2018. Three sources defined pharmacogenomic actionability: FDA labels, Clinical Pharmacogenetics Implementation Consortium guidelines, and our institutionally-deliverable pharmacogenomic clinical decision support (CDS) summaries. A subset of patients (validation cohort) had previously undergone broad, preemptive pharmacogenomic testing within other clinics but results were unavailable within rheumatology. We assessed the occurrence of specific pharmacogenomic ADRs/IRs in this group.
RESULTS
From 174,834 prescribing events, 6300/7761 patients (81%) had clinically actionable pharmacogenomic drug prescriptions (i.e. institutional CDS summaries would have been deployable if testing had been done). Using more conservative standards (pharmacogenomically actionable by ≥2 guidance bodies), 4158/7761 (54%) patient prescriptions could have been impacted. The greatest proportions of potentially impacted rheumatologic prescriptions were for tramadol (47%), allopurinol (21%), azathioprine (17%) and celecoxib (8%). Among our validation cohort (94 previously-genotyped patients), 29 (31%) patients had a pharmacogenomic genotype that would have cautioned possible ADRs/IRs for ≥1 medication. Four patients actually suffered ADRs/IRs that would have been predicted by preemptive genotyping.
CONCLUSIONS
Pharmacogenomic genotyping could inform prescribing for the majority of rheumatology patients and may prevent a subset of ADRs/IRs. These findings justify prospective evaluation of pharmacogenomic testing including assessment of cost-effectiveness in selected rheumatology populations to further understand impact on therapy-related toxicities and treatment outcomes.
Topics: Adult; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacogenetics; Pharmacogenomic Testing; Rheumatology
PubMed: 33506753
DOI: 10.55563/clinexprheumatol/e3hfts -
The Journal of Molecular Diagnostics :... Mar 2022Clinical pharmacogenomic testing typically uses targeted genotyping, which only detects variants included in the test design and may vary among laboratories. To evaluate...
Clinical pharmacogenomic testing typically uses targeted genotyping, which only detects variants included in the test design and may vary among laboratories. To evaluate the potential patient impact of genotyping compared with sequencing, which can detect common and rare variants, an in silico targeted genotyping panel was developed based on the variants most commonly included in clinical tests and applied to a cohort of 10,030 participants who underwent sequencing for CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, DPYD, SLCO1B1, TPMT, UGT1A1, and VKORC1. The results of in silico targeted genotyping were compared with the clinically reported sequencing results. Of the 10,030 participants, 2780 (28%) had at least one potentially clinically relevant variant/allele identified by sequencing that would not have been detected in a standard targeted genotyping panel. The genes with the largest number of participants with variants only detected by sequencing were SLCO1B1, DPYD, and CYP2D6, which affected 13%, 6.3%, and 3.5% of participants, respectively. DPYD (112 variants) and CYP2D6 (103 variants) had the largest number of unique variants detected only by sequencing. Although targeted genotyping detects most clinically significant pharmacogenomic variants, sequencing-based approaches are necessary to detect rare variants that collectively affect many patients. However, efforts to establish pharmacogenomic variant classification systems and nomenclature to accommodate rare variants will be required to adopt sequencing-based pharmacogenomics.
Topics: Alleles; Cytochrome P-450 CYP2D6; Genotype; Humans; Liver-Specific Organic Anion Transporter 1; Pharmacogenetics; Pharmacogenomic Testing; Vitamin K Epoxide Reductases
PubMed: 35041929
DOI: 10.1016/j.jmoldx.2021.11.008 -
Pharmacogenomics Aug 2021The application of pharmacogenomics could meaningfully contribute toward medicines optimization within primary care. This review identified 13 studies describing eight... (Review)
Review
The application of pharmacogenomics could meaningfully contribute toward medicines optimization within primary care. This review identified 13 studies describing eight implementation models utilizing a multi-gene pharmacogenomic panel within a primary care or community setting. These were small feasibility studies (n <200). They demonstrated importance and feasibility of pre-test counseling, the role of the pharmacist, data integration into the electronic medical record and point-of-care clinical decision support systems (CDSS). Findings were considered alongside existing primary care prescribing practices and implementation frameworks to demonstrate how issues may be addressed by existing nationalized healthcare and primary care infrastructure. Development of point-of-care CDSS should be prioritized; establishing clinical leadership, education programs, defining practitioner roles and responsibilities and addressing commissioning issues will also be crucial.
Topics: Decision Support Systems, Clinical; Drug Prescriptions; Humans; Pharmacists; Pharmacogenetics; Pharmacogenomic Testing; Primary Health Care
PubMed: 34467776
DOI: 10.2217/pgs-2021-0032 -
Pharmacogenomics Jun 2019The appropriate use and integration of pharmacogenetic (PGx) testing will pivot on provider preparation and training. Pharmacists have been recognized as one of the key...
The appropriate use and integration of pharmacogenetic (PGx) testing will pivot on provider preparation and training. Pharmacists have been recognized as one of the key providers in the delivery of PGx testing and as such, professional organizations have recommended inclusion of PGx content in pharmacy curricula. We reviewed the curriculum of 132 US pharmacy schools for information about PGx courses. A total of 70 core curriculum courses were identified. 55 (42%) pharmacy schools included at least one PGx course as part of the core curriculum, and ten (8%) schools that offered a PGx course elective. While many pharmacy schools have responded to the accreditation standards to include PGx, less than half of the schools have developed a standalone course.
Topics: Curriculum; Education, Pharmacy; Pharmacogenetics; Pharmacogenomic Testing; Precision Medicine; Schools, Pharmacy; Students, Pharmacy; United States
PubMed: 31250728
DOI: 10.2217/pgs-2019-0024 -
Pharmacogenomics Feb 2022To evaluate the potential impact of preemptive multigene pharmacogenomic (PGx) testing on medication prescribing in real-world clinical settings. Prescription...
To evaluate the potential impact of preemptive multigene pharmacogenomic (PGx) testing on medication prescribing in real-world clinical settings. Prescription frequencies for 65 medications with actionable PGx recommendations were collected in 215 percutaneous coronary intervention (PCI) and 131 allogeneic hematopoietic cell transplant (allo-HCT) patients. A simulation projected the number of PGx-guided prescribing opportunities. In PCI and allo-HCT patients, respectively, 66.5 and 90.1% were prescribed at least one medication with actionable PGx prescribing recommendations. Simulations projected 26.5 and 41.2 total PGx-guided prescribing opportunities per 100 PCI and allo-HCT patients, respectively, if multigene PGx results were available. A multigene PGx testing strategy offers potential to optimize medication prescribing beyond clopidogrel and tacrolimus in PCI and allo-HCT patients.
Topics: Bone Marrow Transplantation; Clopidogrel; Drug Prescriptions; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Percutaneous Coronary Intervention; Pharmacogenomic Testing; Platelet Aggregation Inhibitors; Tacrolimus
PubMed: 35083934
DOI: 10.2217/pgs-2021-0125 -
Pharmacogenomics Jun 2021Combination drug therapies have become an integral part of precision oncology, and while evidence of clinical effectiveness continues to grow, the underlying mechanisms... (Review)
Review
Combination drug therapies have become an integral part of precision oncology, and while evidence of clinical effectiveness continues to grow, the underlying mechanisms supporting synergy are poorly understood. Immortalized human lymphoblastoid cell lines (LCLs) have been proven as a particularly useful, scalable and low-cost model in pharmacogenetics research, and are suitable for elucidating the molecular mechanisms of synergistic combination therapies. In this review, we cover the advantages of LCLs in synergy pharmacogenomics and consider recent studies providing initial evidence of the utility of LCLs in synergy research. We also discuss several opportunities for LCL-based systems to address gaps in the research through the expansion of testing regimens, assessment of new drug classes and higher-order combinations, and utilization of integrated omics technologies.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Humans; Lymphocytes; Pharmacogenomic Testing
PubMed: 34044623
DOI: 10.2217/pgs-2020-0160 -
Translational Psychiatry Mar 2022The pharmacological treatment of depression consists of stages of trial and error, with less than 40% of patients achieving remission during first medication trial.... (Randomized Controlled Trial)
Randomized Controlled Trial
The pharmacological treatment of depression consists of stages of trial and error, with less than 40% of patients achieving remission during first medication trial. However, in a large, randomized-controlled trial (RCT) in the U.S. ("GUIDED"), significant improvements in response and remission rates were observed in patients who received treatment guided by combinatorial pharmacogenomic testing, compared to treatment-as-usual (TAU). Here we present results from the Canadian "GAPP-MDD" RCT. This 52-week, 3-arm, multi-center, participant- and rater-blinded RCT evaluated clinical outcomes among patients with depression whose treatment was guided by combinatorial pharmacogenomic testing compared to TAU. The primary outcome was symptom improvement (change in 17-item Hamilton Depression Rating Scale, HAM-D17) at week 8. Secondary outcomes included response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. Numerically, patients in the guided-care arm had greater symptom improvement (27.6% versus 22.7%), response (30.3% versus 22.7%), and remission rates (15.7% versus 8.3%) compared to TAU, although these differences were not statistically significant. Given that the GAPP-MDD trial was ultimately underpowered to detect statistically significant differences in patient outcomes, it was assessed in parallel with the larger GUIDED RCT. We observed that relative improvements in response and remission rates were consistent between the GAPP-MDD (33.0% response, 89.0% remission) and GUIDED (31.0% response, 51.0% remission) trials. Together with GUIDED, the results from the GAPP-MDD trial indicate that combinatorial pharmacogenomic testing can be an effective tool to help guide depression treatment in the context of the Canadian healthcare setting (ClinicalTrials.gov NCT02466477).
Topics: Antidepressive Agents; Canada; Depression; Depressive Disorder, Major; Humans; Pharmacogenomic Testing; Treatment Outcome
PubMed: 35288545
DOI: 10.1038/s41398-022-01847-8 -
Molecular Omics Aug 2018The toxicogenomics field aims to understand and predict toxicity by using 'omics' data in order to study systems-level responses to compound treatments. In recent years... (Review)
Review
The toxicogenomics field aims to understand and predict toxicity by using 'omics' data in order to study systems-level responses to compound treatments. In recent years there has been a rapid increase in publicly available toxicological and 'omics' data, particularly gene expression data, and a corresponding development of methods for its analysis. In this review, we summarize recent progress relating to the analysis of RNA-Seq and microarray data, review relevant databases, and highlight recent applications of toxicogenomics data for understanding and predicting compound toxicity. These include the analysis of differentially expressed genes and their enrichment, signature matching, methods based on interaction networks, and the analysis of co-expression networks. In the future, these state-of-the-art methods will likely be combined with new technologies, such as whole human body models, to produce a comprehensive systems-level understanding of toxicity that reduces the necessity of in vivo toxicity assessment in animal models.
Topics: Animals; Databases, Genetic; Drug Discovery; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Humans; Pharmacogenomic Testing; Systems Biology; Toxicity Tests; Toxicogenetics
PubMed: 29917034
DOI: 10.1039/c8mo00042e -
Clinical Pharmacology and Therapeutics Sep 2021Pharmacogenetics (PGx) seeks to enable selection of the right dose of the right drug for each patient to optimize therapeutic outcomes. Most PGx focuses on... (Review)
Review
Pharmacogenetics (PGx) seeks to enable selection of the right dose of the right drug for each patient to optimize therapeutic outcomes. Most PGx focuses on pharmacokinetics (PKs), due to our relatively advanced understanding of the genes involved in PKs and the causative effects of variants in those genes. Genetic variants can also affect pharmacodynamics (PDs), but relatively few PGx-PD associations have been identified. This is partially due to a more limited understanding of the relevant genes and the consequences of genetic variation, but is also due in part to the potential confounding of PK variability in assessments of clinical outcomes that have a contribution from both PKs and PDs. For example, it is challenging to confirm the effect of mu opioid receptor (OPRM1) genetic variation on opioid response due to the contribution of CYP2D6 genotype to bioactivation of some opioid drugs (i.e., codeine and tramadol). The objectives of this mini-review are to describe several recent efforts to discover and validate PGx-PD that disentangle the influence of PK variability and propose potential approaches that could be used in future PGx-PD analyses. We use the effect of OPRM1 genetics on opioid response to illustrate how these analyses could be conducted and conclude by discussing how PGx-PD could be translated into clinical practice to improve therapeutic outcomes.
Topics: Analgesics, Opioid; Genetic Variation; Genotype; Humans; Pharmacogenetics; Pharmacogenomic Testing; Receptors, Opioid, mu
PubMed: 34043820
DOI: 10.1002/cpt.2312