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Frontiers in Pharmacology 2023[This corrects the article DOI: 10.3389/fphar.2023.1178421.].
[This corrects the article DOI: 10.3389/fphar.2023.1178421.].
PubMed: 37719864
DOI: 10.3389/fphar.2023.1274075 -
British Journal of Clinical Pharmacology Feb 2024This study aimed to provide up-to-date information on paediatric population pharmacokinetic models of tacrolimus and to identify factors influencing tacrolimus...
AIMS
This study aimed to provide up-to-date information on paediatric population pharmacokinetic models of tacrolimus and to identify factors influencing tacrolimus pharmacokinetic variability.
METHODS
Systematic searches in the Web of Science, PubMed, Scopus, Science Direct, Cochrane, EMBASE databases and reference lists of articles were conducted from inception to March 2023. All population pharmacokinetic studies of tacrolimus using nonlinear mixed-effect modelling in paediatric solid organ transplant patients were included.
RESULTS
Of the 21 studies reviewed, 62% developed from liver transplant recipients and 33% from kidney transplant recipients. Most studies used a 1-compartment model to describe tacrolimus pharmacokinetics. Body weight was a significant predictor for tacrolimus volume of distribution (Vd/F). The estimated Vd/F for 1-compartment models ranged from 20 to 1890 L, whereas the peripheral volume of distribution (Vp/F) for 2-compartment models was between 290 and 1520 L. Body weight, days post-transplant, CYP3A5 genotype or haematocrit were frequently reported as significant predictors of tacrolimus clearance. The estimated apparent clearance values range between 0.12 and 2.18 L/h/kg, with inter-individual variability from 13.5 to 110.0%. Only 29% of the studies assessed the generalizability of the models with external validation.
CONCLUSION
This review highlights the potential factors, modelling approaches and validation methods that impact tacrolimus pharmacokinetics in a paediatric population. The clinician could predict tacrolimus clearance based on body weight, CYP3A5 genotype, days post-transplant or haematocrit. Further research is required to determine the relationship between pharmacogenetics and tacrolimus pharmacodynamics in paediatric patients and confirm the applicability of nonlinear kinetics in this population.
Topics: Child; Humans; Body Weight; Cytochrome P-450 CYP3A; Genotype; Immunosuppressive Agents; Kidney Transplantation; Models, Biological; Organ Transplantation; Polymorphism, Single Nucleotide; Tacrolimus; Transplant Recipients
PubMed: 37714740
DOI: 10.1111/bcp.15909 -
The International Journal of... Oct 2023The clinical heterogeneity in major depressive disorder (MDD), variable treatment response, and conflicting findings limit the ability of genomics toward the discovery...
BACKGROUND
The clinical heterogeneity in major depressive disorder (MDD), variable treatment response, and conflicting findings limit the ability of genomics toward the discovery of evidence-based diagnosis and treatment regimen. This study attempts to curate all genetic association findings to evaluate potential variants for clinical translation.
METHODS
We systematically reviewed all candidates and genome-wide association studies for both MDD susceptibility and antidepressant response, independently, using MEDLINE, particularly to identify replicated findings. These variants were evaluated for functional consequences using different in silico tools and further estimated their diagnostic predictability by calculating positive predictive values.
RESULTS
A total of 217 significantly associated studies comprising 1200 variants across 545 genes and 128 studies including 921 variants across 412 genes were included with MDD susceptibility and antidepressant response, respectively. Although the majority of associations were confirmed by a single study, we identified 31 and 18 replicated variants (in at least 2 studies) for MDD and antidepressant response. Functional annotation of these 31 variants predicted 20% coding variants as deleterious/damaging and 80.6% variants with regulatory effect. Similarly, the response-related 18 variants revealed 25% coding variant as damaging and 88.2% with substantial regulatory potential. Finally, we could calculate the diagnostic predictability of 19 and 5 variants whose positive predictive values ranges from 0.49 to 0.66 for MDD and 0.36 to 0.66 for response.
CONCLUSIONS
The replicated variants presented in our data are promising for disease diagnosis and improved response outcomes. Although these quantitative assessment measures are solely directive of available observational evidence, robust homogenous validation studies are required to strengthen these variants for molecular diagnostic application.
Topics: Humans; Depressive Disorder, Major; Genome-Wide Association Study; Antidepressive Agents
PubMed: 36655406
DOI: 10.1093/ijnp/pyad001 -
Nature. Mental Health 2024Pharmacogenomics could optimize antipsychotic treatment by preventing adverse drug reactions, improving treatment efficacy or relieving the cost burden on the healthcare...
Pharmacogenomics could optimize antipsychotic treatment by preventing adverse drug reactions, improving treatment efficacy or relieving the cost burden on the healthcare system. Here we conducted a systematic review to investigate whether pharmacogenetic testing in individuals undergoing antipsychotic treatment influences clinical or economic outcomes. On 12 January 2024, we searched MEDLINE, EMBASE, PsycINFO and Cochrane Centrale Register of Controlled Trials. The results were summarized using a narrative approach and summary tables. In total, 13 studies were eligible for inclusion in the systematic review. The current evidence base is either in favor of pharmacogenetics-guided prescribing or showed no difference between pharmacogenetics and treatment as usual for clinical and economic outcomes. In the future, we require randomized controlled trials with sufficient sample sizes that provide recommendations for patients who take antipsychotics based on a broad, multigene panel, with consistent and comparable clinical outcomes.
PubMed: 38746691
DOI: 10.1038/s44220-024-00240-2 -
Journal of the Chinese Medical... Jan 2024Vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) are a common cancer treatment. However, the pharmacologic characteristics of VEGF-TKIs may... (Meta-Analysis)
Meta-Analysis
Major adverse cardiovascular events of vascular endothelial growth factor tyrosine kinase inhibitors among patients with different malignancy: A systemic review and network meta-analysis.
BACKGROUND
Vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) are a common cancer treatment. However, the pharmacologic characteristics of VEGF-TKIs may influence cardiovascular risks. The relative risks of major adverse cardiovascular events (MACEs) associated with VEGF-TKIs are poorly understood.
METHODS
We searched PubMed, Embase, and ClinicalTrials.gov from inception until August 31, 2021, for phase II/III randomized controlled trials of 11 VEGF-TKIs (axitinib, cabozantinib, lenvatinib, pazopanib, ponatinib, ripretinib, regorafenib, sorafenib, sunitinib, tivozanib, and vandetanib). The endpoints were heart failure, thromboembolism, and cardiovascular death. The Mantel-Haenszel method was used to calculate the risk of VEGF-TKI among users by comparing it to nonusers. Pairwise meta-analyses with a random-effects model were used to estimate the risks of the various VEGF-TKIs. We estimated ranked probability with a P-score and assessed credibility using the Confidence in Network Meta-Analysis framework.
RESULTS
We identified 69 trials involving 30 180 patients with cancer. The highest risk of MACEs was associated with high-potency tivazonib (odds ratio [OR]: 3.34), lenvatinib (OR: 3.26), and axitinib (OR: 2.04), followed by low-potency pazopanib (OR: 1.79), sorafenib (OR: 1.77), and sunitinib (OR: 1.66). The risk of heart failure significantly increased in association with less-selective sorafenib (OR: 3.53), pazopanib (OR: 3.10), and sunitinib (OR: 2.65). The risk of thromboembolism significantly increased in association with nonselective lenvatinib (OR: 3.12), sorafenib (OR: 1.54), and sunitinib (OR: 1.53). Higher potency (tivozanib, axitinib) and lower selectivity (sorafenib, vandetanib, pazopanib, sunitinib) were associated with a higher probability of heart failure. Low selectivity (lenvatinib, cabozantinib, sorafenib, sunitinib) was associated with a higher probability of thromboembolism.
CONCLUSION
Higher-potency and lower-selectivity VEGF-TKIs may influence the risks of MACEs, heart failure, and thromboembolism. These findings may facilitate evidence-based decision-making in clinical practice.
Topics: Humans; Sunitinib; Antineoplastic Agents; Vascular Endothelial Growth Factor A; Sorafenib; Tyrosine Kinase Inhibitors; Axitinib; Network Meta-Analysis; Protein Kinase Inhibitors; Neoplasms; Heart Failure; Thromboembolism
PubMed: 37991373
DOI: 10.1097/JCMA.0000000000001026 -
Clinical and Translational Science Jun 2024For the same age, sex, and dosage, there can be significant variation in fertility outcomes in childhood cancer survivors. Genetics may explain this variation. This...
For the same age, sex, and dosage, there can be significant variation in fertility outcomes in childhood cancer survivors. Genetics may explain this variation. This study aims to: (i) review the genetic contributions to infertility, (ii) search for pharmacogenomic studies looking at interactions of cancer treatment, genetic predisposition and fertility-related outcomes. Systematic searches in MEDLINE Ovid, Embase Classic+Embase, and PubMed were conducted using the following selection criteria: (i) pediatric, adolescent, and young adult cancer survivors, below 25 years old at the time of diagnosis, (ii) fertility outcome measures after cancer therapy, (iii) genetic considerations. Studies were excluded if they were (i) conducted in animal models, (ii) were not published in English, (iii) editorial letters, (iv) theses. Articles were screened in Covidence by at least two independent reviewers, followed by data extraction and a risk of bias assessment using the Quality in Prognostic Studies tool. Eight articles were reviewed with a total of 29 genes. Outcome measures included sperm concentration, azoospermia, AMH levels, assessment of premature menopause, ever being pregnant or siring a pregnancy. Three studies included replication cohorts, which attempted replication of SNP findings for NPY2R, BRSK1, FANCI, CYP2C19, CYP3A4, and CYP2B6. Six studies were rated with a high risk of bias. Differing methods may explain a lack of replication, and small cohorts may have contributed to few significant findings. Larger, prospective longitudinal studies with an unbiased genome-wide focus will be important to replicate significant results, which can be applied clinically.
Topics: Adolescent; Child; Female; Humans; Male; Young Adult; Antineoplastic Agents; Cancer Survivors; Fertility; Infertility; Neoplasms; Pharmacogenetics; Pharmacogenomic Testing
PubMed: 38924306
DOI: 10.1111/cts.13827 -
European Neuropsychopharmacology : the... Apr 2024The aim of the study was to assess the clinical utility of currently available pharmacogenomic (PGx) tools compared with treatment as usual (TAU), using a meta-analysis... (Meta-Analysis)
Meta-Analysis
Current level of evidence for improvement of antidepressant efficacy and tolerability by pharmacogenomic-guided treatment: A Systematic review and meta-analysis of randomized controlled clinical trials.
The aim of the study was to assess the clinical utility of currently available pharmacogenomic (PGx) tools compared with treatment as usual (TAU), using a meta-analysis of dichotomous and continuous antidepressant efficacy and tolerability data from previously published clinical trials. MEDLINE, clinicaltrial.gov, EU Clinical Trials Register, WHO ICTRP and CENTRAL were systematically searched; of the 962 results originally reviewed, 15 trials were included. Antidepressant efficacy was quantified by relative and absolute changes in symptom severity after eight weeks of treatment and by response and remission rates, while tolerability was estimated by the rate of study discontinuation for any reason. In the PGx-guided patients, symptom severity reduced by an average of 31.0% after eight weeks of treatment, compared to an average reduction of 26.8% in the TAU group. Accordingly, PGx-guided patients experienced a greater reduction in symptom severity of 3.4% (95%CI: 1.6-5.3%), which corresponded to a reduction in the Hamilton Depression score of 0.75 (0.30-1.21), a 37% (15-63%) higher remission rate, and an 18% (5-33%) higher response rate compared with TAU patients, while no difference was observed in discontinuation rate between groups. Notably, the majority of associations lost statistical significance when restricting the dataset to low risk of bias studies, while certain funnel plots suggested a potential publication bias favoring the reporting of statistically significant results. In summary, PGx tools marginally enhance antidepressant efficacy, but not antidepressant tolerability; thus, additional research and advancement of PGx tools are needed to improve integration of PGx in clinical pharmacotherapy of depression.
Topics: Humans; Pharmacogenetics; Antidepressive Agents
PubMed: 38340605
DOI: 10.1016/j.euroneuro.2024.01.005 -
Ophthalmic Research 2024Anti-vascular endothelial growth factor (anti-VEGF) agents have a variable effect on patients with age-related macular degeneration (AMD) that has been attributed to... (Meta-Analysis)
Meta-Analysis Review
Association of the Complement Factor H Y402H Polymorphism and Response to Anti-Vascular Endothelial Growth Factor Treatment in Age-Related Macular Degeneration: An Updated Meta-Analysis.
INTRODUCTION
Anti-vascular endothelial growth factor (anti-VEGF) agents have a variable effect on patients with age-related macular degeneration (AMD) that has been attributed to several causes, including genetic factors. We evaluated the effects of Complement Factor H (CFH) rs1061170/Y402H polymorphism on the response to anti-VEGF therapy among AMD patients.
METHODS
PubMed, Scopus, EMBASE, Web of Science, and Google Scholar were used for a literature search. Pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated to assess the effects of CFH Y402H polymorphism on the response to anti-VEGF therapy in AMD. I2 was used to present the amount of heterogeneity. We used STATA version 14.0 software.
RESULTS
Twenty-five papers reporting data for 4,681 patients were included in this study. Better response to anti-VEGF therapy was seen in T over C (OR = 1.25, 95% CI = 1.04-1.50), TT over CC (OR = 1.60, 95% CI = 1.06-2.4), and TT + TC over CC (OR = 1.68, 95% CI = 1.23-2.28) genotypes. There was no significant difference in the three other genetic models (TT vs. TC, TT vs. TC + CC, TC vs. TT + CC). In Asians, no significant difference was observed in all six genetic models. Ranibizumab and bevacizumab had similar efficacy; however, conbercept was more effective in homozygous genotypes. The literature indicated that TT and TC genotypes and T allele were associated with a better functional response, while the CC genotype and C alleles had a better anatomical response. The combination of risk alleles in ARMS2 A69S (rs10490924), VEGF-A (rs699947), and VEGF-A (rs833069) with Y420H is a predictor of non-respondents.
CONCLUSION
In patients with AMD, the CFH Y402H is a predictor of the response to anti-VEGF agents and should be considered in the treatment plan.
Topics: Humans; Complement Factor H; Vascular Endothelial Growth Factor A; Angiogenesis Inhibitors; Polymorphism, Single Nucleotide; Macular Degeneration; Genotype
PubMed: 38754401
DOI: 10.1159/000539377 -
Genes Oct 2023In the 20 years since the initial sequencing of the human genome, genomics has become increasingly relevant to nursing. We sought to chart the current state of genomics...
In the 20 years since the initial sequencing of the human genome, genomics has become increasingly relevant to nursing. We sought to chart the current state of genomics in nursing by conducting a systematic scoping review of the literature in four databases (2012-2022). The included articles were categorized according to the Cochrane Collaboration outcome domains/sub-domains, and thematic analysis was employed to identify key topical areas to summarize the state of the science. Of 8532 retrieved articles, we identified 232 eligible articles. The articles primarily reported descriptive studies from the United States and other high-income countries (191/232, 82%). More than half (126/232, 54.3%) aligned with the "healthcare provider oriented outcomes" outcome domain. Three times as many articles related to the "knowledge and understanding" sub-domain compared to the "consultation process" subdomain (96 vs. 30). Five key areas of focus were identified, including "nursing practice" (50/126, 40%), "genetic counseling and screening" (29/126, 23%), "specialist nursing" (21/126, 17%), "nurse preparatory education" (17/126, 13%), and "pharmacogenomics" (9/126, 7%). Only 42/126 (33%) articles reported interventional studies. To further integrate genomics into nursing, study findings indicate there is a need to move beyond descriptive work on knowledge and understanding to focus on interventional studies and implementation of genomics into nursing practice.
Topics: Humans; United States; Educational Status; Health Personnel; Genomics
PubMed: 38002957
DOI: 10.3390/genes14112013 -
European Journal of Human Genetics :... Feb 2024The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize...
The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the gene-drug interaction of ABCG2 with allopurinol, HLA-B with allopurinol, MTHFR with folic acid, and MTHFR with methotrexate, relevant for the treatment of gout, cancer, and rheumatoid arthritis. A systematic review was performed based on which pharmacotherapeutic recommendations were developed. Allopurinol is less effective in patients with the ABCG2 p.(Gln141Lys) variant. In HLA-B*58:01 carriers, the risk of severe cutaneous adverse events associated with allopurinol is strongly increased. The DPWG recommends using a higher allopurinol dose in patients with the ABCG2 p.(Gln141Lys) variant. For HLA-B*58:01 positive patients the DPWG recommends choosing an alternative (for instance febuxostat). The DPWG indicates that another option would be to precede treatment with allopurinol tolerance induction. Genotyping of ABCG2 in patients starting on allopurinol was judged to be 'potentially beneficial' for drug effectiveness, meaning genotyping can be considered on an individual patient basis. Genotyping for HLA-B*58:01 in patients starting on allopurinol was judged to be 'beneficial' for drug safety, meaning it is advised to consider genotyping the patient before (or directly after) drug therapy has been initiated. For MTHFR-folic acid there is evidence for a gene-drug interaction, but there is insufficient evidence for a clinical effect that makes therapy adjustment useful. Finally, for MTHFR-methotrexate there is insufficient evidence for a gene-drug interaction.
Topics: Humans; Allopurinol; ATP Binding Cassette Transporter, Subfamily G, Member 2; Drug Interactions; Folic Acid; Gout Suppressants; HLA-B Antigens; Methotrexate; Methylenetetrahydrofolate Reductase (NADPH2); Neoplasm Proteins; Pharmacogenetics
PubMed: 36056234
DOI: 10.1038/s41431-022-01180-0