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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 -
Research in Social & Administrative... Nov 2023The field of pharmacogenomics is rapidly advancing, but its adoption and implementation remain slow and lacking. Lack of pharmacogenomics knowledge among healthcare... (Review)
Review
BACKGROUND
The field of pharmacogenomics is rapidly advancing, but its adoption and implementation remain slow and lacking. Lack of pharmacogenomics knowledge among healthcare professionals is the most frequently cited barrier to adopting and implementing pharmacogenomics in clinical settings.
OBJECTIVES
This study aimed to critically evaluate and determine the effectiveness of educational interventions in improving pharmacogenomics knowledge and practice.
METHODS
Four electronic databases were searched: MEDLINE, EMBASE, CENTRAL, and PsycINFO. Studies on pharmacogenomics educational interventions for health care professionals and students with pre- and post-intervention assessments and results were included. No restrictions were placed on time, language, or educational contexts. The educational outcomes measured include both objective and subjective outcomes. The pharmacogenomics competency domains used to judge educational interventions are based on the competency domains listed by the American Association of Colleges of Pharmacies (AACP). The National Heart, Lung, and Blood Institute of the National Institutes of Health was used for the quality assessment of pre-post studies with no control group and the controlled intervention studies. No meta-analysis was conducted; the data were synthesized qualitatively. The systematic review was reported in accordance with the PRISMA statement.
RESULTS
Fifty studies were included in this review. All included studies integrated the AACP pharmacogenomics competency domains into their educational interventions. Most of the studies had educational interventions that integrated clinical cases (n = 44; 88%). Knowledge was the most frequently evaluated outcome (n = 34; 68%) and demonstrated significant improvement after the educational intervention that integrated AACP pharmacogenomics competency domains and employed active learning with clinical case inclusion.
CONCLUSION
This review provided evidence of the effectiveness of educational interventions in improving pharmacogenomics knowledge and practice. Incorporating pharmacogenomics competency domains into education and training, with patient cases for healthcare professionals and students, dramatically improved their pharmacogenomics knowledge, attitudes, and confidence in practice.
Topics: Humans; Pharmacogenetics; Students; Health Personnel; Educational Status; Delivery of Health Care
PubMed: 37586945
DOI: 10.1016/j.sapharm.2023.07.012 -
Frontiers in Public Health 2023Variants in organic cation transporter (OCT) genes play a crucial role in metformin pharmacokinetics and are critical for diabetes treatment. However, studies... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Variants in organic cation transporter (OCT) genes play a crucial role in metformin pharmacokinetics and are critical for diabetes treatment. However, studies investigating the effect of OCT genetic polymorphisms on metformin response have reported inconsistent results. This review and meta-analysis aimed to evaluate the associations between OCT genetic polymorphisms and metformin response and intolerance in individuals with type 2 diabetes mellitus (T2DM).
METHOD
A systematic search was conducted on PubMed, EMBASE, CNKI, WANFANG DATA, and VIP database for identifying potential studies up to 10 November 2022. The Q-Genie tool was used to evaluate the quality of included studies. Pooled odds ratios (OR) or standardized mean differences (SMD) and 95% confidence intervals (95% CI) were calculated to determine the associations between OCT genetic polymorphisms and metformin response and intolerance that were reflected by glycemic response indexes, such as glycated hemoglobin level (HbA1c%) or change in glycated hemoglobin level (ΔHbA1c%), fasting plasma level (FPG) or change in fasting plasma glucose level (ΔFPG), the effectiveness rate of metformin treatment, and the rate of metformin intolerance. A qualitative review was performed for the variants identified just in one study and those that could not undergo pooling analysis.
RESULTS
A total of 30 related eligible studies about OCT genes (, and ) and metformin pharmacogenetics were identified, and 14, 3, and 6 single nucleotide polymorphisms (SNPs) in , and , respectively, were investigated. Meta-analysis showed that the rs622342 polymorphism was associated with a reduction in HbA1c level (AA vs. AC: SMD [95% CI] = -0.45 [-0.73--0.18]; = 0.001). The GG genotype of the rs628031 polymorphism was associated with a reduction in FPG level (GG vs. AA: SMD [95 %CI] = -0.60 [-1.04-0.16], = 0.007; GG vs. AG: -0.45 [-0.67-0.20], < 0.001). No statistical association was found between the remaining variants and metformin response and intolerance.
CONCLUSION
rs622342 and rs628031 polymorphisms were potentially associated with glycemic response to metformin. This evidence may provide novel insight into gene-oriented personalized medicine for diabetes.
Topics: Humans; Metformin; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Hypoglycemic Agents; Polymorphism, Single Nucleotide; Cations
PubMed: 37546319
DOI: 10.3389/fpubh.2023.1183879 -
Frontiers in Pharmacology 2023Taxane-induced peripheral neuropathy (TIPN) is an important cause of premature treatment cessation and dose-limitation in cancer therapy. It also reduces quality of...
Taxane-induced peripheral neuropathy (TIPN) is an important cause of premature treatment cessation and dose-limitation in cancer therapy. It also reduces quality of life and survivorship in affected patients. Genetic polymorphisms in the CYP3A family have been investigated but the findings have been inconsistent and contradictory. A systematic review identified 12 pharmacogenetic studies investigating genetic variation in and and TIPN. In our candidate gene study, 288 eligible participants (211 taxane participants receiving docetaxel or paclitaxel, and 77 control participants receiving oxaliplatin) were successfully genotyped for and . Genotyping data was transformed into a combined CYP3A metaboliser phenotype: Poor metabolisers, intermediate metabolisers and extensive metabolisers. Individual genotypes and combined CYP3A metaboliser phenotypes were assessed in relation to neurotoxicity, including by meta-analysis where possible. In the systematic review, no significant association was found between and TIPN in seven studies, with one study reporting a protective association. For , one study has reported an association with TIPN, while four other studies failed to show an association. Evaluation of our patient cohort showed that paclitaxel was found to be more neurotoxic than docetaxel ( < 0.001). Diabetes was also significantly associated with the development of TIPN. The candidate gene analysis showed no significant association between either SNP () and the development of TIPN overall, or severe TIPN. Meta-analysis showed no association between these two variants and TIPN. Transformed into combined CYP3A metaboliser phenotypes, 30 taxane recipients were poor metabolisers, 159 were intermediate metabolisers, and 22 were extensive metabolisers. No significant association was observed between metaboliser status and case-control status. We have shown that the risk of peripheral neuropathy during taxane chemotherapy is greater in patients who have diabetes. CYP3A genotype or phenotype was not identified as a risk factor in either the candidate gene analysis or the systematic review/meta-analysis, although we cannot exclude the possibility of a minor contribution, which would require a larger sample size.
PubMed: 37469869
DOI: 10.3389/fphar.2023.1178421 -
Journal of Crohn's & Colitis Dec 2023Nudix hydrolase 15 [NUDT15] genetic variants confer an increased risk of thiopurine-induced leukopenia [TIL]; however, their global prevalence in inflammatory bowel... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Nudix hydrolase 15 [NUDT15] genetic variants confer an increased risk of thiopurine-induced leukopenia [TIL]; however, their global prevalence in inflammatory bowel disease [IBD] patients is unknown. We aimed to evaluate the global prevalence of NUDT15 variants in IBD patients and incidence of TIL in these patients.
METHODS
Six databases were searched from inception until July 2022. Studies reporting the frequency of any NUDT15 variant and/or frequency of leukopenia in adult IBD patients with these variants were included. A random effects model was performed to estimate the pooled prevalence of variants, incidence of early [≤8 weeks] and late [>8 weeks] leukopenia, and relative risk of developing leukopenia.
RESULTS
Twenty studies comprising 5232 patients were included. The pooled prevalence of the *1/*3 c.415C > T C/T diplotype was 13% (95% confidence interval [CI]: 10-18%), *3/*3 c.415C > T T/T diplotype was 2% [95% CI: 1-2%], *1/*5 c.52G > A G/A diplotype was 2% [95% CI: 1-3%], and *1/*6 c.36_37insGGAGTC ins/- diplotype was 7% [95% CI: 4-12%]. The pooled prevalence of *1/*3 was high in Japanese [20%, 95% CI: 16-24%] and Chinese patients [18%, 95% CI: 12-27%]. The incidence of early leukopenia was 20% [95% CI: 16-26%] in *1/*3 patients, 99% [95% CI: 7-100%] in *3/*3 patients, and 49% [95% CI: 29-69%] in *1/*6 patients. The incidence of late leukopenia was 36% [95% CI: 26-49%] in *1/*3 patients.
CONCLUSIONS
NUDT15 variants are common and strongly predict TIL in IBD patients. Pre-treatment NUDT15 genotyping should be considered particularly in Asian populations, to guide thiopurine dosing and prevent myelotoxicity.
Topics: Adult; Humans; Mercaptopurine; Incidence; Prevalence; Genetic Predisposition to Disease; Risk Factors; Pyrophosphatases; Inflammatory Bowel Diseases; Leukopenia; Purines; Sulfhydryl Compounds
PubMed: 37346013
DOI: 10.1093/ecco-jcc/jjad107 -
Biomedicine & Pharmacotherapy =... Aug 2023Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare disease, but it is one of the most common inflammatory neuropathies in the population. It is... (Review)
Review
BACKGROUND
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare disease, but it is one of the most common inflammatory neuropathies in the population. It is particularly common among patients with diabetes mellitus. This raises many problems, both with the differential diagnosis of diabetic and inflammatory neuropathy, as well as the choice of treatment. Intravenous immunoglobulin (IVIG) is one of the therapeutic options. There is evidence for the effectiveness of IVIG in treating about two-thirds of patients. However, no review has been published to date systematising studies evaluating the response to IVIG treatment in patients with CIDP and coexisting diabetes.
METHODS
The present study is based on the PRISMA statement and is registered at PROSPERO (CRD42022356180). The study included searches of the databases of MEDLINE, ERIC, CINAHL Complete, Academic Search Ultimate and Health Source: Nursing/Academic Edition, finally including seven original papers evaluating a total of 534 patients in the review. The main inclusion criteria were the presence of a group of patients with CIDP and comorbid diabetes in the study.
RESULTS
The systematic review showed a lower efficacy of IVIG treatment among patients with coexisting diabetes compared with idiopathic CIDP (61 % vs 71 %). In addition, the presence of conduction blocks on neurography and shorter disease duration proved to be significant factors improving response to treatment.
CONCLUSIONS
Current scientific data do not allow for strong recommendations on the choice of treatment for CIDP. A randomised, multicentre study evaluating the efficacy of different therapeutic approaches to this disease entity needs to be planned.
Topics: Humans; Immunoglobulins, Intravenous; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Infusions, Intravenous; Administration, Intravenous; Diabetes Mellitus; Multicenter Studies as Topic
PubMed: 37290187
DOI: 10.1016/j.biopha.2023.114974 -
The Pharmacogenomics Journal Sep 2023Pharmacogenomics (PGx) is rapidly growing branch of molecular genetics with high potentials to influence therapeutics. This review evaluates knowledge and attitudes of... (Meta-Analysis)
Meta-Analysis
Pharmacogenomics (PGx) is rapidly growing branch of molecular genetics with high potentials to influence therapeutics. This review evaluates knowledge and attitudes of medical and pharmacy students about PGx. A literature search was conducted in electronic databases and studies were selected by following precise eligibility criteria. After quality assessment, studies were reviewed systematically, and meta-analyses of proportions were performed to estimate response rates of students. Fifteen studies (5509 students; 69% [95% confidence interval (CI): 60%, 77%] females) were included. Among students, 28% [95%CI: 12, 46] had adequate PGx knowledge; 65% [95%CI: 55, 75] were willing to have PGx test for their own risk assessment; 78% [95%CI: 71, 84] had intention to incorporate PGx in future practice; and 32% [95%CI: 21, 43] were satisfied with current PGx component of curriculum. Age, advanced year of educational program, and more time spent in PGx education were positively associated with PGx knowledge and positive attitudes.
Topics: Female; Humans; Male; Pharmacogenetics; Students, Pharmacy; Attitude; Curriculum; Intention
PubMed: 37142641
DOI: 10.1038/s41397-023-00306-x -
European Journal of Human Genetics :... Mar 2024The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate pharmacogenetics implementation in clinical practice by developing evidence-based guidelines to...
The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate pharmacogenetics implementation in clinical practice by developing evidence-based guidelines to optimize pharmacotherapy. A guideline describing the gene-drug interaction between the genes CYP2D6, CYP3A4 and CYP1A2 and antipsychotics is presented here. The DPWG identified gene-drug interactions that require therapy adjustments when respective genotype is known for CYP2D6 with aripiprazole, brexpiprazole, haloperidol, pimozide, risperidone and zuclopenthixol, and for CYP3A4 with quetiapine. Evidence-based dose recommendations were obtained based on a systematic review of published literature. Reduction of the normal dose is recommended for aripiprazole, brexpiprazole, haloperidol, pimozide, risperidone and zuclopenthixol for CYP2D6-predicted PMs, and for pimozide and zuclopenthixol also for CYP2D6 IMs. For CYP2D6 UMs, a dose increase or an alternative drug is recommended for haloperidol and an alternative drug or titration of the dose for risperidone. In addition, in case of no or limited clinical effect, a dose increase is recommended for zuclopenthixol for CYP2D6 UMs. Even though evidence is limited, the DPWG recommends choosing an alternative drug to treat symptoms of depression or a dose reduction for other indications for quetiapine and CYP3A4 PMs. No therapy adjustments are recommended for the other CYP2D6 and CYP3A4 predicted phenotypes. In addition, no action is required for the gene-drug combinations CYP2D6 and clozapine, flupentixol, olanzapine or quetiapine and also not for CYP1A2 and clozapine or olanzapine. For identified gene-drug interactions requiring therapy adjustments, genotyping of CYP2D6 or CYP3A4 prior to treatment should not be considered for all patients, but on an individual patient basis only.
Topics: Humans; Antipsychotic Agents; Aripiprazole; Clopenthixol; Clozapine; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Drug Interactions; Haloperidol; Olanzapine; Pharmacogenetics; Pimozide; Quetiapine Fumarate; Quinolones; Risperidone; Thiophenes
PubMed: 37002327
DOI: 10.1038/s41431-023-01347-3 -
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 -
European Archives of Psychiatry and... Oct 2023Evidence regarding effectiveness and safety of clozapine once- vs. multiple-daily dosing is limited. We compared demographic and clinical parameters between patients... (Meta-Analysis)
Meta-Analysis
Evidence regarding effectiveness and safety of clozapine once- vs. multiple-daily dosing is limited. We compared demographic and clinical parameters between patients with once- vs. multiple-daily dosing in the Department of Psychiatry and Psychotherapy, University of Regensburg, Germany (AGATE dataset), and the Department of Psychiatry, Lausanne University Hospital, Switzerland, using non-parametric tests. Effectiveness and safety outcomes were available in the AGATE dataset. We performed a systematic review in PubMed/Embase until February 2022, meta-analyzing studies comparing clozapine once- vs. multiple-daily-dosing. We estimated a pooled odds ratio for adverse drug-induced reactions (ADRs) and meta-analyzed differences regarding clinical symptom severity, age, percentage males, smokers, clozapine dose, and co-medications between patients receiving once- vs. multiple-daily dosing. Study quality was assessed using the Newcastle-Ottawa-Scale. Of 1494 and 174 patients included in AGATE and Lausanne datasets, clozapine was prescribed multiple-daily in 74.8% and 67.8%, respectively. In the AGATE cohort, no differences were reported for the clinical symptoms severity or ADR rate (p > 0.05). Meta-analyzing eight cohorts with a total of 2810 clozapine-treated individuals, we found more severe clinical symptoms (p = 0.036), increased ADR risk (p = 0.01), higher clozapine doses (p < 0.001), more frequent co-medication with other antipsychotics (p < 0.001), benzodiazepines (p < 0.001), anticholinergics (p = 0.039), and laxatives (p < 0.001) in patients on multiple- vs. once-daily dosing. Of six studies, five were rated as good, and one as poor quality. Patients responding less well to clozapine may be prescribed higher doses multiple-daily, also treated with polypharmacy, potentially underlying worse safety outcomes. Patient preferences and adherence should be considered during regimen selection.
Topics: Male; Humans; Clozapine; Cross-Sectional Studies; Antipsychotic Agents; Benzodiazepines; Polypharmacy
PubMed: 36580106
DOI: 10.1007/s00406-022-01542-1