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Clinical and Translational Science Jun 2024Pharmacogenetic testing could reduce the time to identify a safe and effective medication for depression; however, it is underutilized in practice. Major depression...
Pharmacogenetic testing could reduce the time to identify a safe and effective medication for depression; however, it is underutilized in practice. Major depression constitutes the most common mental disorder in the US, and while antidepressant therapy can help, the current trial -and error approach can require patients to endure multiple medication trials before finding one that is effective. Tailoring the fit of pharmacogenetic testing with prescribers' needs across a variety of settings could help to establish a generalizable value proposition to improve likelihood of adoption. We conducted a study to explore the value proposition for health systems using pharmacogenetic testing for mental health medications through prescribers' real-world experiences using implementation science concepts and systematic interviews with prescribers and administrators from four health care systems. To identify a value proposition, we organized the themes according to the Triple Aim framework, a leading framework for health care policy which asserts that high-value care should focus on three key metrics: (1) better health care quality and (2) population-level outcomes with (3) reduced per capita costs. Primary care providers whom we interviewed said that they value pharmacogenetic testing because it would provide more information about medications that they can prescribe, expanding their ability to identify medications that best-fit patients and reducing their reliance on referrals to specialists; they said that this capacity would help meet patients' needs for access to mental health care through primary care. At the same time, prescribers expressed differing views about how pharmacogenetic testing can help with quality of care and whether their views about out-of-pocket cost would prevent them from offering it. Thus, implementation should focus on integrating pharmacogenetic testing into primary care and using strategies to support prescribers' interactions with patients.
Topics: Humans; Pharmacogenomic Testing; Primary Health Care; Antidepressive Agents; Depressive Disorder, Major; Quality of Health Care
PubMed: 38898561
DOI: 10.1111/cts.13837 -
Journal of Infection and Chemotherapy :... Jun 2024Voriconazole pharmacokinetics (PK) are known to be affected by genetic polymorphisms of drug-metabolizing enzymes such as CYP2C19; however, such information is limited...
BACKGROUND
Voriconazole pharmacokinetics (PK) are known to be affected by genetic polymorphisms of drug-metabolizing enzymes such as CYP2C19; however, such information is limited for the pediatric population. The primary aim of this study is to establish a voriconazole PK model incorporating CYP2C19 phenotypes in Japanese children with malignancy or inborn errors of immunity.
METHODS
CYP2C19 genotypes were assessed by whole-genome genotyping and defined as follows: *17/*17: ultrarapid metabolizer (URM), *1/*17: rapid metabolizer (RM), *1/*1:normal metabolizer (NM), *1/*2, *1/*3, *2/*17:intermediate metabolizer (IM), and *2/*2, *2/*3, *3/*3: poor metabolizer (PM). Population PK analysis was performed. The voriconazole serum concentration profile was described by a two-compartment model with first-order absorption, mixed linear and nonlinear (Michaelis-Menten) elimination.
RESULTS
Voriconazole concentration data were available from 60 patients with a median age of 5.3 years. The phenotypes predicted from CYP2C19 genotypes were RM in 1 (2 %), NM in 21 (35 %) patients, IM in 27 (45 %) patients, and PM in 11 (18 %) patients. Underlying diseases included 38 (63%) patients with hematological malignancy and 18 (30 %) patients with inborn errors of immunity. Among the CYP2C19 phenotypes, PM was predicted to show complete inhibition (the degree of V inhibition [V] = 100 %; V = 0). The estimated parameters of V were +0.8 higher in patients with gamma-glutamyl transpeptidase (γ-GTP) Grade 2 or higher and +2.7 higher when C-reactive protein (CRP) levels were 2.0 mg/dL or higher.
CONCLUSION
CYP2C19 genetic polymorphisms, γ-GTP, and CRP affect V of voriconazole in children with malignancy or inborn errors of immunity.
PubMed: 38897411
DOI: 10.1016/j.jiac.2024.06.009 -
Clinical Chemistry and Laboratory... Jun 2024Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of severe fluoropyrimidine-related toxicities. The best strategy for identifying DPD-deficient...
OBJECTIVES
Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of severe fluoropyrimidine-related toxicities. The best strategy for identifying DPD-deficient patients is still not defined. The EMA recommends targeted genotyping or uracilemia (U) testing. We analyzed the concordance between both approaches.
METHODS
This study included 19,376 consecutive French patients with pre-treatment plasma U, UH2 and targeted genotyping (*2A, *13, D949V, *7) analyzed at Eurofins Biomnis (2015-2022).
RESULTS
Mean U was 9.9 ± 10.1 ng/mL (median 8.7, range 1.6-856). According to French recommendations, 7.3 % of patients were partially deficient (U 16-150 ng/mL) and 0.02 % completely deficient (U≥150 ng/mL). variant frequencies were *2A: 0.83 %, *13: 0.17 %, D949V: 1.16 %, *7: 0.05 % (2 homozygous patients with U at 22 and 856 ng/mL). Variant carriers exhibited higher U (median 13.8 vs. 8.6 ng/mL), and lower UH2/U (median 7.2 vs. 11.8) and UH2/U (median 0.54 vs. 1.37) relative to wild-type patients (p<0.00001). Sixty-six% of variant carriers exhibited uracilemia <16 ng/mL, challenging correct identification of DPD deficiency based on U. The sensitivity (% patients with a deficient phenotype among variant carriers) of U threshold at 16 ng/mL was 34 %. The best discriminant marker for identifying variant carriers was UH2/U. UH2/U<0.942 (29.7 % of patients) showed enhanced sensitivity (81 %) in identifying deleterious genotypes across different variants compared to 16 ng/mL U.
CONCLUSIONS
These results reaffirm the poor concordance between DPD phenotyping and genotyping, suggesting that both approaches may be complementary and that targeted genotyping is not sufficiently reliable to identify all patients with complete deficiency.
PubMed: 38896022
DOI: 10.1515/cclm-2024-0317 -
Clinical Pharmacology and Therapeutics Jun 2024The ability of freely available in silico tools to predict the effect of non-synonymous single nucleotide polymorphisms (nsSNPs) in pharmacogenes on protein function is...
The ability of freely available in silico tools to predict the effect of non-synonymous single nucleotide polymorphisms (nsSNPs) in pharmacogenes on protein function is not well defined. We assessed the performance of seven sequence-based (SIFT, PolyPhen2, mutation accessor, FATHMM, PhD-SNP, MutPred2, and SNPs & Go) and five structure-based (mCSM, SDM, DDGun, CupSat, and MAESTROweb) tools in predicting the impact of 118 nsSNPs in the CYP2C19, CYP2C9, CYP2B6, CYP2D6, and DPYD genes with known function (24 normal, one increased, 42 decreased, and 51 no-function). Sequence-based tools had a higher median (IQR) positive predictive value (89% [89-94%] vs. 12% [10-15%], P < 0.001) and lower negative predictive value (30% [24-34%] vs. 90% [80-93%], P < 0.001) than structure-based tools. Accuracy did not significantly differ between sequence-based (59% [37-67%]) and structure-based (34% [23-44%]) tools (P = 0.070). Notably, the no-function CYP2C9*3 allele and decreased function CYP2C9*8 allele were predicted incorrectly as tolerated by 100% of sequenced-based tools and as stabilizing by 60% and 20% of structure-based tools, respectively. As a case study, we performed mutational analysis for the CYP2C9*1, *3 (I359L), and *8 (R150H) proteins through molecular dynamic (MD) simulations using S-warfarin as the substrate. The I359L variant increased the distance of the major metabolic site of S-warfarin to the oxy-ferryl center of CYP2C9, and I359L and R150H caused shifts in the conformation of S-warfarin to a position less favorable for metabolism. These data suggest that MD simulations may better capture the impact of nsSNPs in pharmacogenes than other tools.
PubMed: 38894625
DOI: 10.1002/cpt.3348 -
Clinical and Translational Science Jun 2024Genetic screening for HLA-B*15:02 before prescribing carbamazepine is standard practice to prevent severe cutaneous adverse reactions in Asian populations. These...
Genetic screening for HLA-B*15:02 before prescribing carbamazepine is standard practice to prevent severe cutaneous adverse reactions in Asian populations. These reactions are associated not only with this allele but also with closely related HLA-B75 serotype markers-HLA-B*15:11 and HLA-B*15:21-which are prevalent in several Asian countries. However, a reliable method for identifying HLA-B75 serotype markers is still not available. We developed an in-house quantitative PCR (qPCR) for HLA-B75 screening and validated it using 303 anonymized DNA samples. Due to inadequate quality control, the qPCR results for 11 samples were excluded. We analyzed the sensitivity and specificity of the test using 93 HLA-typed samples. The concordance between the qPCR method and an established screening method was assessed using 199 HLA-screened samples tested for HLA-B*15:02 at Songklanagarind Hospital, Songkhla, Thailand. All discordant results were confirmed by Sanger sequencing. The qPCR method demonstrated a sensitivity of 100% (95% confidence interval = 83.16%-100.00%) and a specificity of 100% (95% confidence interval = 95.07%-100.00%). Concordance analysis revealed a 96.5% agreement between methods (192/199; 44 positive and 148 negative results). All discordant results were due to HLA-B75 markers not being HLA-B*15:02 (two samples with HLA-B*15:11 and five samples with HLA-B*15:21). In conclusion, this qPCR method could be useful for identifying HLA-B75 carriers at risk of carbamazepine-induced reactions in Asian populations where carriers of HLA-B*15:02, HLA-B*15:11, or HLA-B*15:21 are common.
Topics: Humans; Carbamazepine; HLA-B15 Antigen; Real-Time Polymerase Chain Reaction; Thailand; Anticonvulsants; Asian People; Pharmacogenetics; Serogroup; Sensitivity and Specificity; Alleles
PubMed: 38894615
DOI: 10.1111/cts.13867 -
Nutrients May 2024This study aimed to compare and relate the body composition (obtained through anthropometry with the pentacompartmental model and the tricompartmental model by DXA) with...
This study aimed to compare and relate the body composition (obtained through anthropometry with the pentacompartmental model and the tricompartmental model by DXA) with bone mineral density and biochemical and nutritional parameters in Chilean adults with overweight/obesity and normal weight from La Araucanía region, Chile. A case-control study was conducted with 116 adults and volunteers from the PURE cohort, collecting sociodemographic data, BMI assessment, waist-to-hip ratio (WHR), and body composition using the pentacompartmental model (5CM) and tricompartmental model (3CM) by DXA, as well as bone mineral density (BMD). Blood biochemical parameters (fasting glucose and lipid profile), physical activity (PA) measured by GPAQ, and average dietary habits (R24h) were measured. In the overweight/obesity group, the 5CM and 3CM adipose mass were indirectly and moderately correlated with PA ( < 0.05), except in the male 5CM group. In the overweight/obesity group, muscle and fat-free mass (FFM) of the 5CM and 3CM correlated directly and moderately with blood fasting glucose (BFG) and BMD ( < 0.05), except in females, where FFM was not related to BMD but was related to residual mass ( < 0.01). Independent of gender and BMI, bone mineral content was positively and highly correlated with BMD ( < 0.0000). In the male overweight/obesity group, bone, skin, and residual mass were correlated with BFG ( < 0.05). In conclusion, for the assessment of non-athletic adult populations, more routine use of the 5CM in clinical practice is recommended.
Topics: Humans; Bone Density; Male; Female; Chile; Adult; Body Composition; Obesity; Case-Control Studies; Middle Aged; Overweight; Nutritional Status; Absorptiometry, Photon; Blood Glucose; Body Mass Index; Exercise
PubMed: 38892493
DOI: 10.3390/nu16111559 -
International Journal of Molecular... May 2024This ABIGENE pharmacokinetic (PK) study sought mainly to characterize the unchanged drug PK during long-term abiraterone acetate (AA) administration in advanced prostate...
This ABIGENE pharmacokinetic (PK) study sought mainly to characterize the unchanged drug PK during long-term abiraterone acetate (AA) administration in advanced prostate cancer patients (81 patients). It was observed that individual AA concentrations remained constant over treatment time, with no noticeable changes during repeated long-term drug administration for up to 120 days. There was no correlation between AA concentrations and survival outcomes. However, a significant association between higher AA concentrations and better clinical benefit was observed ( = 0.041). The safety data did not correlate with the AA PK data. A significant positive correlation (r = 0.40, < 0.001) was observed between mean AA concentration and patient age: the older the patient, the higher the AA concentration. Patient age was found to impact steady-state AA concentration: the older the patient, the higher the mean AA concentration. Altogether, these data may help to guide future research and clinical trials in order to maximize the benefits of AA metastatic castration-resistant prostate cancer patients.
Topics: Humans; Male; Abiraterone Acetate; Prostatic Neoplasms, Castration-Resistant; Aged; Middle Aged; Aged, 80 and over; Follow-Up Studies; Neoplasm Metastasis; Antineoplastic Agents
PubMed: 38892246
DOI: 10.3390/ijms25116058 -
International Journal of Molecular... May 2024This review emphasises the importance of opioid monitoring in clinical practice and advocates for a personalised approach based on pharmacogenetics. Beyond effectively... (Review)
Review
This review emphasises the importance of opioid monitoring in clinical practice and advocates for a personalised approach based on pharmacogenetics. Beyond effectively managing pain, meticulous oversight is required to address concerns about side effects, specially due to opioid-crisis-related abuse and dependence. Various monitoring techniques, along with pharmacogenetic considerations, are critical for personalising treatment and optimising pain relief while reducing misuse and addiction risks. Future perspectives reveal both opportunities and challenges, with advances in analytical technologies holding promise for increasing monitoring efficiency. The integration of pharmacogenetics has the potential to transform pain management by allowing for a precise prediction of drug responses. Nevertheless, challenges such as prominent pharmacogenetic testing and guideline standardisation persist. Collaborative efforts are critical for transforming scientific advances into tangible improvements in patient care. Standardised protocols and interdisciplinary collaboration are required to ensure consistent and evidence-based opioid monitoring. Future research should look into the long-term effects of opioid therapy, as well as the impact of genetic factors on individual responses, to help guide personalised treatment plans and reduce adverse events. Lastly, embracing innovation and collaboration can improve the standard of care in chronic pain management by striking a balance between pain relief and patient safety.
Topics: Humans; Analgesics, Opioid; Precision Medicine; Pain Management; Drug Monitoring; Chronic Pain; Pharmacogenetics; Opioid-Related Disorders
PubMed: 38892112
DOI: 10.3390/ijms25115925 -
International Journal of Molecular... May 2024Genetic biomarkers could potentially lower the risk of treatment failure in chronic inflammatory diseases (CID) like psoriasis, psoriatic arthritis (PsA), rheumatoid... (Meta-Analysis)
Meta-Analysis Review
The Association between Genetics and Response to Treatment with Biologics in Patients with Psoriasis, Psoriatic Arthritis, Rheumatoid Arthritis, and Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis.
Genetic biomarkers could potentially lower the risk of treatment failure in chronic inflammatory diseases (CID) like psoriasis, psoriatic arthritis (PsA), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). We performed a systematic review and meta-analysis assessing the association between single nucleotide polymorphisms (SNPs) and response to biologics. Odds ratio (OR) with 95% confidence interval (CI) meta-analyses were performed. In total, 185 studies examining 62,774 individuals were included. For the diseases combined, the minor allele of MYD88 (rs7744) was associated with good response to TNFi (OR: 1.24 [1.02-1.51], 6 studies, 3158 patients with psoriasis or RA) and the minor alleles of NLRP3 (rs4612666) (OR: 0.71 [0.58-0.87], 5 studies, 3819 patients with RA or IBD), TNF-308 (rs1800629) (OR: 0.71 [0.55-0.92], 25 studies, 4341 patients with psoriasis, RA, or IBD), FCGR3A (rs396991) (OR: 0.77 [0.65-0.93], 18 studies, 2562 patients with psoriasis, PsA, RA, or IBD), and TNF-238 (rs361525) (OR: 0.57 [0.34-0.96]), 7 studies, 818 patients with psoriasis, RA, or IBD) were associated with poor response to TNFi together or infliximab alone. Genetic variants in TNFα, NLRP3, MYD88, and FcRγ genes are associated with response to TNFi across several inflammatory diseases. Most other genetic variants associated with response were observed in a few studies, and further validation is needed.
Topics: Humans; Inflammatory Bowel Diseases; Psoriasis; Polymorphism, Single Nucleotide; Biological Products; Arthritis, Rheumatoid; Arthritis, Psoriatic; NLR Family, Pyrin Domain-Containing 3 Protein; Myeloid Differentiation Factor 88
PubMed: 38891983
DOI: 10.3390/ijms25115793 -
International Journal of Molecular... May 2024Aminobisphosphonates (NBPs) are the first-choice medication for osteoporosis (OP); NBP treatment aims at increasing bone mineral density (BMD) by inhibiting the activity...
Aminobisphosphonates (NBPs) are the first-choice medication for osteoporosis (OP); NBP treatment aims at increasing bone mineral density (BMD) by inhibiting the activity of farnesyl diphosphate synthase (FDPS) enzyme in osteoclasts. Despite its efficacy, inadequate response to the drug and side effects have been reported. The A allele of the rs2297480 (A > C) SNP, found in the regulatory region of the gene, is associated with reduced gene transcription. This study evaluates the variant rs2297480 (A > C) association with OP patients' response to alendronate sodium treatment. A total of 304 OP patients and 112 controls were enrolled; patients treated with alendronate sodium for two years were classified, according to BMD variations at specific regions (lumbar spine (L1-L4), femoral neck (FN) and total hip (TH), as responders (OP-R) ( = 20) and non-responders (OP-NR) ( = 40). We observed an association of CC genotype with treatment failure ( = 0.045), followed by a BMD decrease in the regions L1-L4 (CC = -2.21% ± 2.56; = 0.026) and TH (CC = -2.06% ± 1.84; = 0.015) after two years of alendronate sodium treatment. Relative expression of the gene was also evaluated in OP-R and OP-NR patients. Higher expression of the gene was also observed in OP-NR group (FC = 1.84 ± 0.77; = 0.006) when compared to OP-R. In conclusion, the influence observed of expression and the rs2897480 variant on alendronate treatment highlights the importance of a genetic approach to improve the efficacy of treatment for primary osteoporosis.
Topics: Humans; Alendronate; Bone Density; Female; Geranyltranstransferase; Male; Osteoporosis; Aged; Treatment Failure; Middle Aged; Polymorphism, Single Nucleotide; Bone Density Conservation Agents; Genotype; Alleles; Case-Control Studies
PubMed: 38891810
DOI: 10.3390/ijms25115623