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Yudisia Ausi,1,2 Melisa Intan Barliana,2,3 Maarten J Postma,3,4 Auliya A Suwantika3,5 1Doctor Program in Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia; 2Department of Biological Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia; 3Center of Excellence for Pharmaceutical Care Innovation, Universitas Padjadjaran, Bandung, Indonesia; 4Department of Health Sciences, University Medical Center Groningen, University of Groningen, Groningen, Netherlands; 5Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, IndonesiaCorrespondence: Auliya A Suwantika, Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jalan Raya Bandung Sumedang KM 21 Jatinangor, Sumedang, 45363, Indonesia, Tel +62 22 84288828, Email auliya@unpad.ac.idAbstract: Pharmacogenetics is a promising approach in future personalized medicine. This field holds excellent prospects for healthcare quality acceleration. It promotes the transition to the precision medicine era, whereby a health treatment is driven by a deeper understanding of individual characteristics by interpreting the underlying genomic variation. Pharmacogenetics has been developing rapidly since the human genome project. Many pharmacogenetics studies have shown the association between genetic variants and therapy outcomes. Several pharmacogenetics working groups have recommended guidelines for the clinical application of pharmacogenetics. However, the development of pharmacogenetics in low- and middle-income countries (LMICs) is still retarded behind. The problems mainly include clinical evidence, technology, policy and regulation, and human resources. Currently, available genome and drug effect data in LMICs are scarce. Pharmacogenetics development should be escalated with evidence proof through research collaboration across countries. The challenges of pharmacogenetics implementation are discussed comprehensively in this article, along with the prospect of pharmacogenetics-guided personalized medicine in developed countries. Stepwise is expected to help the researchers and stakeholders define the problem that hindered the pharmacogenetics application.Keywords: pharmacogenetics, implementation, LMICs, personalized medicine

Abstract Background There is no doubt that genetic factors have the potential to predict the therapeutic outcomes of antidepressants in patients with major depressive disorder (MDD). This study investigated the association between genetic variants involved in serotonin signaling and brain-derived neurotrophic factor (BDNF) with the response to escitalopram treatment in patients with MDD. We focused on examining the influence of 5-HTTLPR (ins/del), HTR2A rs9316233, BDNF rs962369, CYP2C19 and CYP2D6 on the clinical response to escitalopram. Methods The patients were recruited from outpatient psychiatric clinics in Košice between 2020 and 2022. Patients received escitalopram for 12 weeks at a fixed dose of 10 mg daily. Clinical assessment was done at baseline and after 4, 8, and 12 weeks using the 21-item Hamilton Depression Rating Scale (HAMD-21). Results At the end of week 12, 57 (65%) patients were defined as responders to escitalopram treatment, while 31 (35%) patients were non-responders. Genotyping revealed that carriers of the short allele (S) of 5-HTTLPR exhibit a significantly lower therapeutic response to escitalopram measured by HAMD-21 than the long allele (L) carriers (p = 0.01). Adjusting for CYP2C19 and CYP2D6 metabolizer genotypes did not modify the observed relationship between 5-HTTLPR and treatment response. No significant associations were found for HTR2A rs9316233 or BDNF rs962369 variants and the treatment response. Conclusions These findings underscore the utility of 5-HTTLPR genotyping in guiding escitalopram therapy for MDD patients. Further research with larger cohorts is warranted to validate these results and elucidate additional genetic determinants of antidepressant efficacy.

Abstract While significant strides have been made in understanding pharmacogenetics (PGx) and gene-drug interactions, there remains limited characterization of population-level PGx variation. This study aims to comprehensively profile global star alleles (haplotype patterns) and phenotype frequencies in 58 pharmacogenes associated with drug absorption, distribution, metabolism, and excretion. PyPGx, a star-allele calling tool, was employed to identify star alleles within high-coverage whole genome sequencing (WGS) data from the 1000 Genomes Project (N = 2504; 26 global populations). This process involved detecting structural variants (SVs), such as gene deletions, duplications, hybrids, as well as single nucleotide variants and insertion-deletion variants. The majority of our PyPGx calls for star alleles and phenotype frequencies aligned with the Pharmacogenomics Knowledge Base, although notable population-specific frequencies differed at least twofold. Validation efforts confirmed known SVs while uncovering several novel SVs currently undefined as star alleles. Additionally, we identified 210 small nucleotide variants associated with severe functional consequences that are not defined as star alleles. The study serves as a valuable resource, providing updated population-level star allele and phenotype frequencies while incorporating SVs. It also highlights the burgeoning potential of cost-effective WGS for PGx genotyping, offering invaluable insights to improve tailored drug therapies across diverse populations.

Metabolic syndrome (MetS) presents a significant global health challenge, characterized by a cluster of metabolic alterations including obesity, hypertension, insulin resistance/dysglycemia, and atherogenic dyslipidemia. Advances in understanding and pharmacotherapy have added complexity to MetS management, particularly concerning drug interactions and pharmacogenetic variations. Limited literature exists on drug–drug–gene interactions (DDGIs) and drug–drug–transporter gene interactions (DDTGIs), which can significantly impact pharmacokinetics and pharmacodynamics, affecting treatment outcomes. This narrative review aims to address the following three key objectives: firstly, shedding a light on the PK metabolism, transport, and the pharmacogenetics (PGx) of medicines most commonly used in the MetS setting (relevant lipid-lowering drugs, antihypertensives and antihyperglycemics agents); secondly, exemplifying potential clinically relevant pharmacokinetic drug interactions, including drug–drug interactions, DDGIs, and DDTGIs; and, thirdly, describing and discussing their potential roles in clinical practice. This narrative review includes relevant information found with the use of interaction checkers, pharmacogenetic databases, clinical pharmacogenetic practice guidelines, and literature sources, guided by evidence-based medicine principles.

Genetic factors influence medication response (pharmacogenetics), affecting the pharmacodynamics and pharmacokinetics of many medicaments used in clinical care. The ability of medications to cross the blood–brain barrier (BBB) represents a critical putative factor in the effectiveness and tolerability of various medications relevant to central nervous system disorders (CNS), cancer, and broader medical conditions at a pharmacokinetic (dosing) level. Pharmacogenetics has the potential to personalise medicine to a greater extent than has been possible, with the potential to help reduce heuristic delays to effective tolerable pharmacotherapy. Here, we critically examine and summarise the evidence, particularly for ABCB1 polymorphisms associated with drug transportation and other clinical relevance. These transporters appear to have a role in BBB pharmacogenetics and may indicate new avenues of research that extend beyond the current paradigm of CYP450 polymorphisms. We identify some of the most promising variants for clinical translation while spotlighting the complexities of the involved systems and limitations of the current empirical literature.

Schizophrenia is a highly heritable, severe mental illness characterized by hallucinations, delusions, social withdrawal, and cognitive dysfunction present in ∼1% of populations across cultures. There have been recent major advancements in our understanding of the genetic architecture of schizophrenia. Both rare, highly penetrant genetic variants as well as common, low-penetrant genetic variants can predispose individuals to schizophrenia and can impact the way people metabolize psychoactive medications used to treat schizophrenia. However, the impact of these findings on the clinical management of schizophrenia remains limited. This review highlights the few places where genetics currently informs schizophrenia management strategies, discusses major limitations, and reviews promising areas of genetics research that are most likely to impact future schizophrenia care. Specifically, I focuss on psychiatric genetic counseling, genetic testing strategies, pharmacogenetics, polygenic risk, and genetics-guided treatment. Lastly, I emphasize important ethical considerations in the clinical use of genetics for schizophrenia management, including the exacerbation of healthcare inequalities and unintended consequences of new genetic technologies.

Currently, 30–50 % of individuals with depression and 40 % with anxiety—collectively referred to as common mental disorders (CMDs), exhibit inadequate responses to antidepressant treatments. To assess the effectiveness and safety of drug-metabolizing enzyme pharmacogenetic variation informed treatment (PGxIT) versus usual antidepressant treatment (UT) in patients with CMDs. A literature search was conducted in the MEDLINE, Scopus, and Cochrane Library databases from inception until January 30, 2024. Studies were selected based on CMD diagnoses, reporting on the genetic variations of drug-metabolizing enzyme (DME) genes in relation to antidepressants, involving PGxIT and UT groups with human subjects, and published in English. Data extraction and quality assessment were performed independently by two authors. A pooled risk ratio (RR) with 95 % CI was estimated using both random and fixed-effect models, and heterogeneity was assessed using Cochran's Q test and the I2 statistic. The publication bias of eligible studies was assessed using post hoc Doi plots and the LFK index. This systematic review included 18 studies (n = 7021). The PGxIT demonstrated greater efficacy in the remission of symptoms of depressive disorder at 8 weeks (RR 1.523 [95 % CI: 1.255–1.843]; I2 = 48 %) and 12 weeks (RR 1.631 [95 % CI: 1.001–2.657]; I2 = 86 %; p < 0.01), and symptoms of anxiety disorder compared to UT. Additionally, the risk of adverse drug events (ADEs) was significantly lower in the PGxIT group (RR = 0.65 [95 % CI: 0.52–0.82]; I2 = 0 %) than in the UT group. The certainty of evidence for both outcomes was moderate. This systematic review and meta-analysis suggest that pharmacogenetically guided antidepressant treatment, based on genetic variation in drug-metabolizing enzymes, is associated with superior efficacy in the remission of symptoms for patients with depressive disorders and a reduction in ADEs compared to usual treatment and the findings of the systematic review for remission in anxiety disorders indicate that, PGx guided treatment is also associated with increased remission of symptoms in anxiety disorders compared to usual treatment. • Up to 30-50% of depression and 40% of anxiety patients show inadequate responses to standard antidepressant treatments. • PGxIT improved depressive disorder remission at 8 and 12 weeks and showed better safety with fewer adverse drug events over UT. • PGxIT also enhanced anxiety disorder remission, but more research is needed to confirm its effectiveness. • Moderate evidence supports PGxIT's benefits for depression, with potential for broader clinical application. [ABSTRACT FROM AUTHOR]

Background: Research on the pharmacogenetic influence of hepatic CYP450 enzyme 2D6 (CYP2D6) on metabolism of drugs for psychosis and associated outcome has been inconclusive. Some results suggest increased risk of adverse reactions in poor and intermediate metabolizers, while others find no relationship. However, retrospective designs may fail to account for the long-term pharmacological treatment of patients. Previous studies found that clinicians adapted risperidone dose successfully without knowledge of patient CYP2D6 phenotype. Aim: Here, we aimed to replicate the results of those studies in a Dutch cohort of patients with psychosis (N = 418) on pharmacological treatment. Method: We compared chlorpromazine-equivalent dose between CYP2D6 metabolizer phenotypes and investigated which factors were associated with dosage. This was repeated in two smaller subsets; patients prescribed pharmacogenetics-actionable drugs according to published guidelines, and risperidone-only as done previously. Results: We found no relationship between chlorpromazine-equivalent dose and phenotype in any sample (complete sample: p = 0.3, actionable-subset: p = 0.82, risperidone-only: p = 0.34). Only clozapine dose was weakly associated with CYP2D6 phenotype (p = 0.03). Conclusion: Clinicians were thus not intuitively adapting dose to CYP2D6 activity in this sample, nor was CYP2D6 activity associated with prescribed dose. Although the previous studies could not be replicated, this study may provide support for existing and future pharmacogenetic research. [ABSTRACT FROM AUTHOR]

Background: Pharmacogenetics is considered a promising avenue for improving treatment outcomes, yet evidence arguing for the use of pharmacogenetics in the treatment of psychotic disorders is mixed and clinical usefulness is under debate. Many patients with psychosis use multiple medications, which can alter the metabolic capacity of CYP enzymes, a process called phenoconversion. In clinical studies, treatment outcomes of drugs for psychosis management may have been influenced by phenoconversion. Aim: Here we evaluate the impact and predictive value of CYP2D6 phenoconversion in patients with psychotic disorders under pharmacological treatment. Method: Phenoconversion-corrected phenotype was determined by accounting for inhibitor strength. Phenoconversion-corrected and genotype-predicted phenotypes were compared in association with side effects, subjective well-being and symptom severity. Results: Phenoconversion led to a large increase in poor metabolizers (PMs; 17–82, 16% of sample), due to concomitant use of the serotonin reuptake inhibitors fluoxetine and paroxetine. Neither CYP2D6-predicted nor phenoconversion-corrected phenotype was robustly associated with outcome measures. Risperidone, however, was most affected by the CYP2D6 genotype. Conclusion: Polypharmacy and phenoconversion were prevalent and accounted for a significant increase in PMs. CYP2D6 may play a limited role in side effects, symptoms and well-being measures. However, due to the high frequency of occurrence, phenoconversion should be considered in future clinical trials. [ABSTRACT FROM AUTHOR]

Objective: Upper gastrointestinal bleeding (UGIB) has been identified as a potential adverse drug reaction associated with the use of low-dose aspirin (LDA). This study aimed to investigate the relationship between variants in the TBXA2R gene, which is involved in platelet aggregation, and the risk of UGIB in patients with cardiovascular diseases treated with LDA. Methods: A case-control study was conducted at a Brazilian hospital complex. Three groups were defined: (1) case group (n = 50): patients with cardiovascular disease who used LDA and were diagnosed with UGIB of non-variceal etiology, (2) LDA control group (n = 50): patients with cardiovascular disease who used LDA without developing UGIB, and (3) healthy control group (n = 189). Data were collected through face-to-face interviews, and blood samples were collected for the analysis of Helicobacter pylori infection and genotyping of 3 genetic variants [rs2238631 (C > T), rs4807491 (A > G), and rs1131882 (A > G)]. Results: The case group had a significantly higher frequency of carriers of the rs4807491.G allele compared to the control group of LDA users (P -value =.004). No significant difference was observed in the proportion of carriers of the rs2238631.T and 1131882.G variants between the studied groups. Carriers of rs2238631.T (OR: 4.515, 95% CI: 1.37-14.89) and rs4807491.G allele (OR: 3.232, 95% CI: 1.12-9.37) exhibited a higher risk of UGIB. Conclusion: These findings suggest that the presence of the rs2238631 and rs4807491 variant alleles is associates with a 3- to 4-fold increased risk of UGIB in patients with cardiovascular diseases treated with LDA. Future studies with larger sample sizes should confirm these results and to better identify individuals who may benefit from chronic LDA use. [ABSTRACT FROM AUTHOR]

Globally, cardio vascular diseases (CVD) remain the primary cause of morbidity and mortality. Pharmacogenomics (PGxs) has profoundly changed how various drug classes are managed in CVDs. For example, genetic polymorphisms in genes such as SLCO1B1 impact how a person responds to statins such as rosuvastatin and atorvastatin, where as the interindividual variability in the reaction to statins (Fluvastatin)used in lipid-lowering therapy can be partly explained by genetic variations in genes encoding drug-metabolizing enzymes such cytochrome P450 and transporters like OATP1B1. Similarly, in antiplatelet therapy, polymorphisms in CYP2C19 affect clopidogrel metabolism, influencing its efficacy in preventing thrombotic events. Genes such as CYP2C9 and VKORC1 are crucial for the metabolism and response to acenocoumarol and warfarin during anticoagulant therapy and monitoring bleeding risk. Genetic variations in CYP2D6 affect the metabolism and effectiveness of propafenone and metoprolol. Understanding the PGx presumptions of these cardiovascular drugs may help develop personalized treatment strategies that lower the possibility of adverse drug reactions, obtain desired therapeutic outcomes, and improve patient compliance and safety with respect to each patient’s unique genetic makeup.

Abstract Background The Alpe-DPD study (NCT02324452) demonstrated that prospective genotyping and dose-individualization using four alleles in DPYD (DPYD*2A/rs3918290, c.1236G > A/rs75017182, c.2846A > T/rs67376798 and c.1679 T > G/rs56038477) can mitigate the risk of severe fluoropyrimidine toxicity. However, this could not prevent all toxicities. The goal of this study was to identify additional genetic variants, both inside and outside DPYD, that may contribute to fluoropyrimidine toxicity. Methods Biospecimens and data from the Alpe-DPD study were used. Exon sequencing was performed to identify risk variants inside DPYD. In silico and in vitro analyses were used to classify DPYD variants. A genome-wide association study (GWAS) with severe fluoropyrimidine-related toxicity was performed to identify variants outside DPYD. Association with severe toxicity was assessed using matched-pair analyses for the exon sequencing and logistic, Cox, and ordinal regression analyses for GWAS. Results Twenty-four non-synonymous, frameshift, and splice site DPYD variants were detected in ten of 986 patients. Seven of these variants (c.1670C > T, c.1913 T > C, c.1925 T > C, c.506delC, c.731A > C, c.1740 + 1G > T, c.763 − 2A > G) were predicted to be deleterious. The carriers of either of these variants showed a trend towards a 2.14-fold (95% CI, 0.41–11.3, P = 0.388) increased risk of severe toxicity compared to matched controls (N = 30). After GWAS of 942 patients, no individual single nucleotide polymorphisms achieved genome-wide significance (P ≤ 5 × 10−8), however, five variants were suggestive of association (P

Abstract Background Human immunodeficiency virus (HIV) and tuberculosis (TB) are major contributors to morbidity and mortality in sub-Saharan Africa including Cameroon. Pharmacogenetic variants could serve as predictors of drug-induced hepatotoxicity (DIH), in patients with TB co-infected with HIV. We evaluated the occurrence of DIH and pharmacogenetic variants in Cameroonian patients. Methods Treatment-naïve patients with HIV, TB or TB/HIV co-infection were recruited at three hospitals in Cameroon, between September 2018 and November 2019. Appropriate treatment was initiated, and patients followed up for 12 weeks to assess DIH. Pharmacogenetic variants were assessed by allele discrimination TaqMan SNP assays. Results Of the 141 treatment naïve patients, the overall incidence of DIH was 38% (53/141). The highest incidence of DIH, 52% (32/61), was observed among HIV patients. Of 32 pharmacogenetic variants, the slow acetylation variants NAT2*5 was associated with a decreased risk of DIH (OR: 0.4; 95%CI: 0.17–0.96; p = 0.038), while NAT2*6 was found to be associated with an increased risk of DIH (OR: 4.2; 95%CI: 1.1–15.2; p = 0.017) among patients treated for TB. Up to 15 SNPs differed in ≥ 5% of allele frequencies among African populations, while 25 SNPs differed in ≥ 5% of the allele frequencies among non-African populations, respectively. Conclusions DIH is an important clinical problem in African patients with TB and HIV. The NAT2*5 and NAT2*6 variants were found to be associated with DIH in the Cameroonian population. Prior screening for the slow acetylation variants NAT2*5 and NAT2*6 may prevent DIH in TB and HIV-coinfected patients.

Asthma is a chronic inflammatory respiratory condition, characterized by variable airflow limitation, leading to clinical symptoms such as dyspnea and chest tightness. These symptoms result from an underlying inflammatory process. The β2 agonists are bronchodilators prescribed for the relief of the disease. Nevertheless, their efficacy exhibits substantial interindividual variability. Currently, there is widespread recognition of the association between specific genetic variants, predominantly located within the ADRB2 and ADCY9 genes and their efficacy. This association, usually represented by the presence of non-synonymous single nucleotide polymorphisms (SNPs) have a strong impact in the protein functionality. The prevalence of these mutations varies based on the ethnic composition of the population and thus understanding the profiles of variability in different populations would contribute significantly to standardizing the use of these medications. In this study, we conducted a sequence-based genotyping of the relevant SNPs within the ADRB2 and ADCY9 genes in patients undergoing treatment with bronchodilators and/or corticosteroids at two healthcare facilities in the state of Rio de Janeiro, Brazil. We investigated the presence of c.46A>G, c.79C>G, c.252G>A, and c.491C>T SNPs within the ADRB2, and c.1320018 A>G within the ADCY9. Our results were in line with existing literature data with both for individuals in Brazil and Latin American.

Abstract Pharmacogenetics investigates sequence of genes that affect drug response, enabling personalized medication. This approach reduces drug-induced adverse reactions and improves clinical effectiveness, making it a crucial consideration for personalized medical care. Numerous guidelines, drawn by global consortia and scientific organizations, codify genotype-driven administration for over 120 active substances. As the scientific community acknowledges the benefits of genotype-tailored therapy over traditionally agnostic drug administration, the push for its implementation into Italian healthcare system is gaining momentum. This evolution is influenced by several factors, including the improved access to patient genotypes, the sequencing costs decrease, the growing of large-scale genetic studies, the rising popularity of direct-to-consumer pharmacogenetic tests, and the continuous improvement of pharmacogenetic guidelines. Since EMA (European Medicines Agency) and AIFA (Italian Medicines Agency) provide genotype information on drug leaflet without clear and explicit clinical indications for gene testing, the regulation of pharmacogenetic testing is a pressing matter in Italy. In this manuscript, we have reviewed how to overcome the obstacles in implementing pharmacogenetic testing in the clinical practice of the Italian healthcare system. Our particular emphasis has been on germline testing, given the absence of well-defined national directives in contrast to somatic pharmacogenetics.

INTRODUCTION. The pathogenesis of antibiotic-associated drug-induced liver injury (DILI) in children has not been fully elucidated to date. Certain genotypes in patients increase the probability of developing DILI. Therefore, the identification of pharmacogenetic markers associated with DILI in children is essential.АIM. This study aimed to identify pharmacogenetic biomarkers of new-onset DILI associated with tigecycline and meropenem in children.MATERIALS AND METHODS. This prospective observational study was conducted in the Morozov Children’s City Clinical Hospital from 1 February 2020 to 1 September 2021. The study analysed the incidence and types of antibiotic-associated adverse drug reactions (ADRs) in 100 critically ill children aged 0 to 17 years (44 boys and 56 girls). Pharmacogenetic testing was performed in children with ADRs (n=30) to identify potential mechanisms involved in the development of their ADRs. The authors isolated and tested DNA from buccal epithelium swabs using the Agena Bioscience iPLEX® PGx Pro-based VeriDose® Core Panel covering 68 single nucleotide polymorphisms (SNPs) or short insertions and deletions (INDELs) and 5 copy number variants (CNVs).RESULTS. The odds of developing DILI associated with meropenem and tigecycline were higher in carriers of the homozygous cytochrome genotype CYP3A5*3/*3 (OR: 12.6; 95% CI: 1.9–79.4, r=6.54, p=0.011) than in patients with the heterozygous genotype CYP3A5*1A/*3. The odds were even higher in patients not carrying the CYP3A5*1A/*3 genotype (OR: 17.14; 95% CI: 1.79–16.3, r=6.24, p=0.013). The detection of the CYP3A5*3/*3 ge­notype had a prognostic accuracy of 76.7%, a sensitivity of 82%, and a specificity of 74% in predicting the risk of DILI associated with meropenem and tigecycline. Moreover, children with DILI carried the heterozygous ge­notype SLCO1B1*1/*5 (rs4149056 polymorphism) more often than children with other adverse reactions ­associated with meropenem and tigecycline (r=9.8, p=0.002).CONCLUSION. The results of this study prove the prognostic significance of the homozygous cytochrome genotype CYP3A*3/*3 as an indicator of a potential risk for developing DILI associated with meropenem and tigecycline in children in critical conditions.The study was registered at ClinicalTrials.gov under No. NCT04141657 on 24 October 2019.

Identification of the genetic features that determine a patient’s individual response to a medicinal product and provision of this information to a doctor helps to predict the effectiveness of therapy and the risk of adverse drug reactions. Dmitry A. Sychev — Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Full Professor, Rector of the Russian Medical Academy of Continuous Professional Education — talks about the importance of a personalised approach to selecting medicinal products and methods for their efficacy and safety control.

Background: Sacituzumab govitecan (sacituzumab) emerged as an important agent in metastatic and locally recurrent HER2‐negative breast cancer treatment. UGT1A1 polymorphisms have also been shown to predict sacituzumab toxicity. Methods: In this retrospective study, we sought to evaluate the associations between UGT1A1 status, toxicity, and therapeutic outcomes in sacituzumab recipients with advanced breast cancer who underwent genotype testing for UGT1A1 alleles (N = 68). Results: We found 17 (25%) of our patients to be homozygous for UGT1A1*28 and 24 (35.3%) were heterozygous. Of seven African American patients with triple‐negative breast cancer, five were homozygous for UGT1A1*28 and two were heterozygous. Patients with a homozygous UGT1A1*28 genotype were significantly more likely to have treatment terminated because of adverse effects. However, the polymorphism was not associated with treatment discontinuation because of disease progression. Conclusion: This retrospective, real‐world analysis suggests potential clinical utility in UGT1A1 testing for patients receiving sacituzumab, but future trials are needed to confirm the association between genotypes and treatment outcomes. [ABSTRACT FROM AUTHOR]

AbstractThis review explores genetic contributors to drug interactions, known as drug-gene and drug-drug-gene interactions (DGI and DDGI, respectively). This article is part of a mini-review issue led by the International Society for the Study of Xenobiotics (ISSX) New Investigators Group. Pharmacogenetics (PGx) is the study of the impact of genetic variation on pharmacokinetics (PK), pharmacodynamics (PD), and adverse drug reactions. Genetic variation in pharmacogenes, including drug metabolizing enzymes and drug transporters, is common and can increase the risk of adverse drug events or contribute to reduced efficacy. In this review, we summarize clinically actionable genetic variants, and touch on methodologies such as genotyping patient DNA to identify genetic variation in targeted genes, and deep mutational scanning as a high-throughput in vitro approach to study the impact of genetic variation on protein function and/or expression in vitro. We highlight the utility of physiologically based pharmacokinetic (PBPK) models to integrate genetic and chemical inhibitor and inducer data for more accurate human PK simulations. Additionally, we analyze the limitations of historical ethnic descriptors in pharmacogenomics research. Altogether, the work herein underscores the importance of identifying and understanding complex DGI and DDGIs with the intention to provide better treatment outcomes for patients. We also highlight current barriers to wide-scale implementation of PGx-guided dosing as standard or care in clinical settings. [ABSTRACT FROM AUTHOR]

Background: The Alpe-DPD study (NCT02324452) demonstrated that prospective genotyping and dose-individualization using four alleles in DPYD (DPYD*2A/rs3918290, c.1236G > A/rs75017182, c.2846A > T/rs67376798 and c.1679 T > G/rs56038477) can mitigate the risk of severe fluoropyrimidine toxicity. However, this could not prevent all toxicities. The goal of this study was to identify additional genetic variants, both inside and outside DPYD, that may contribute to fluoropyrimidine toxicity. Methods: Biospecimens and data from the Alpe-DPD study were used. Exon sequencing was performed to identify risk variants inside DPYD. In silico and in vitro analyses were used to classify DPYD variants. A genome-wide association study (GWAS) with severe fluoropyrimidine-related toxicity was performed to identify variants outside DPYD. Association with severe toxicity was assessed using matched-pair analyses for the exon sequencing and logistic, Cox, and ordinal regression analyses for GWAS. Results: Twenty-four non-synonymous, frameshift, and splice site DPYD variants were detected in ten of 986 patients. Seven of these variants (c.1670C > T, c.1913 T > C, c.1925 T > C, c.506delC, c.731A > C, c.1740 + 1G > T, c.763 − 2A > G) were predicted to be deleterious. The carriers of either of these variants showed a trend towards a 2.14-fold (95% CI, 0.41–11.3, P = 0.388) increased risk of severe toxicity compared to matched controls (N = 30). After GWAS of 942 patients, no individual single nucleotide polymorphisms achieved genome-wide significance (P ≤ 5 × 10−8), however, five variants were suggestive of association (P < 5 × 10−6) with severe toxicity. Conclusions: Results from DPYD exon sequencing and GWAS analysis did not identify additional genetic variants associated with severe toxicity, which suggests that testing for single markers at a population level currently has limited clinical value. Identifying additional variants on an individual level is still promising to explain fluoropyrimidine-related severe toxicity. In addition, studies with larger samples sizes, in more diverse cohorts are needed to identify potential clinically relevant genetic variants related to severe fluoropyrimidine toxicity. [ABSTRACT FROM AUTHOR]

Tramdol is one of most popular opioids used for postoperative analgesia worldwide. Among Arabic countries, there are reports that its dosage is not appropriate due to cultural background. To provide theoretical background of the proper usage of tramadol, this study analyzed the association between several genetic polymorphisms (CYP2D6/OPRM1) and the effect of tramadol. A total of 39 patients who took tramadol for postoperative analgesia were recruited, samples were obtained, and their DNA was extracted for polymerase chain reaction products analysis followed by allelic variations of CYP2D6 and OPRM A118G determination. Numerical pain scales were measured before and 1 h after taking tramadol. The effect of tramadol was defined by the difference between these scales. We concluded that CYP2D6 and OPRM1 A118G single nucleotide polymorphisms may serve as crucial determinants in predicting tramadol efficacy and susceptibility to post-surgical pain. Further validation of personalized prescription practices based on these genetic polymorphisms could provide valuable insights for the development of clinical guidelines tailored to post-surgical tramadol use in the Arabic population. [ABSTRACT FROM AUTHOR]

Cancer is the leading cause of disease-related death among children. Vincristine (VCR), a key component of childhood cancer treatment protocols, is associated with the risk of peripheral neuropathy (PN), a condition that may be reversible upon drug discontinuation but can also leave lasting sequelae. Single nucleotide polymorphism (SNP) in genes involved in VCR pharmacokinetics and pharmacodynamics have been investigated in relation to an increased risk of PN. However, the results of these studies have been inconsistent. A retrospective cohort study was conducted to investigate the potential association of drug transporter genes from the ATP-binding cassette (ABC) family and the centrosomal protein 72 (CEP72) gene with the development of PN in 88 Caucasian children diagnosed with cancer and treated with VCR. Genotyping was performed using real-time PCR techniques for the following SNPs: ABCB1 rs1128503, ABCC1 rs246240, ABCC2 rs717620, and CEP72 rs924607. The results indicated that age at diagnosis (OR = 1.33; 95% CI = 1.07–1.75) and the ABCC1 rs246240 G allele (OR = 12.48; 95% CI = 2.26–100.42) were associated with vincristine-induced peripheral neuropathy (VIPN). No association was found between this toxicity and CEP72 rs924607. Our study provides insights that may contribute to optimizing childhood cancer therapy in the future by predicting the risk of VIPN [ABSTRACT FROM AUTHOR]

Purpose We describe the implementation and ongoing maintenance of CYP2C19 and CYP2D6 focused pharmacogenetic (PGx) testing to guide antidepressant and antianxiety medication prescriptions in a large rural, nonprofit health system. Summary Depression and anxiety are common psychiatric conditions. Sanford Health implemented PGx testing for metabolism of cytochrome P450 (CYP) isozymes 2C19 and 2D6 in 2014 to inform prescribing for multiple medications, including antidepressant and antianxiety therapies. As guidelines, genotype to phenotype translation, panel offerings, and other resources are updated, we adapt our approach. We make educational and informational materials available to providers and patients. Pharmacogenomic clinical pharmacists review PGx results with discrete values and provide guidance documentation in the electronic medical record. A robust clinical decision support system is in place to provide interruptive alerts, noninterruptive alerts, and genomic indicators. A referral-based interdisciplinary clinic is also available to provide in-depth education to patients regarding PGx results and implications. Additionally, partnering with our health plan has expanded access to PGx testing for patients with anxiety or depression. Conclusion The implementation and maintenance of Sanford Health's PGx program to guide antidepressant and antianxiety medication use continues to evolve and requires a multipronged approach relying on both human and informatics-based resources. [ABSTRACT FROM AUTHOR]

Background: Pharmacogenomics (PGx) is a well-established concept of how genes impact medication response, with many studies demonstrating reductions in medication side effects, improved efficacy and cost effectiveness. Despite these benefits, implementation of PGx in daily practice remains limited. Studies on the implementation of PGx in clinical practice have previously found that inadequate knowledge is one of themain barriers. Details regarding specificallywhich educational needs exist among family medicine clinicians requires further study. Objective: The aim of this study was to identify both the perceived role that pharmacogenomics (PGx) could play in primary care practice, the knowledge gaps that family medicine clinicians experience, and the skills they require to use PGx in their daily practice. Methods: To achieve this aim, the attitudes, knowledge, barriers, skills needed, and preferred educational program were explored in a family medicine clinician focus group study via a semi-structured interview and knowledge quiz. Second, multidisciplinary focus groups provided information on the level of knowledge and necessary skills to use PGx in patient care. After gathering key recorded information from both focus groups, the perceived role pharmacogenomics could possibly play in primary care, the predominant knowledge gaps, and the most appropriate educational program was determined by qualitative analysis. Results: Four themes emerged regarding the PGx educational needs and the role of PGx in family medicine: 1) need for PGx competences, 2) insight into the roles and responsibilities of PGx services, 3) optimization of PGx workflow through artificial intelligence integrated in the electronic health record, and 4) the ethical dilemmas and psychological effects related to PGx. These themes reflect a shift in the role of PGx in family medicine with implications for education. Conclusion: The results obtained from this study will help improve the implementation of PGx in daily practice, and consequently, may result in increased utilization of PGx, thereby resulting in improved medication efficacy and reduced side effects. [ABSTRACT FROM AUTHOR]

Background: Sialorrhea is a common and uncomfortable adverse effect of clozapine, and its severity varies between patients. The aim of the study was to select broadly genes related to the regulation of salivation and study associations between sialorrhea and dry mouth and polymorphisms in the selected genes. Methods: The study population consists of 237 clozapine-treated patients, of which 172 were genotyped. Associations between sialorrhea and dry mouth with age, sex, BMI, smoking, clozapine dose, clozapine and norclozapine serum levels, and other comedication were studied. Genetic associations were analyzed with linear and logistic regression models explaining sialorrhea and dry mouth with each SNP added separately to the model as coefficients. Results: Clozapine dose, clozapine or norclozapine concentration and their ratio were not associated with sialorrhea or dryness of mouth. Valproate use (p = 0.013) and use of other antipsychotics (p = 0.015) combined with clozapine were associated with excessive salivation. No associations were found between studied polymorphisms and sialorrhea. In analyses explaining dry mouth with logistic regression with age and sex as coefficients, two proxy-SNPs were associated with dry mouth: epidermal growth factor receptor 4 (ERBB4) rs3942465 (adjusted p = 0.025) and tachykinin receptor 1 (TACR1) rs58933792 (adjusted p = 0.029). Conclusion: Use of valproate or antipsychotic polypharmacy may increase the risk of sialorrhea. Genetic variations in ERBB4 and TACR1 might contribute to experienced dryness of mouth among patients treated with clozapine. [ABSTRACT FROM AUTHOR]

Purpose: The current candidate gene association study aims to investigate tag SNPs from the TACR1 gene as pharmacogenetic predictors of response to the antiemetic guidelines-recommended, NK-1 receptor antagonist-based, triple antiemetic regimens. Methods: A set of eighteen tag SNPs of TACR1 were genotyped in breast cancer patients receiving anthracycline and cyclophosphamide (with/without docetaxel) applying real-time PCR-HRMA. Data analysis for 121 ultimately enrolled patients was initiated by defining haplotype blocks using PHASE v.2.1. The association of each tag SNP and haplotype alleles with failure to achieve the defined antiemetic regimen efficacy endpoints was tested using PLINK (v.1.9 and v.1.07, respectively) based on the logistic regression, adjusting for the previously known chemotherapy-induced nausea and vomiting (CINV) prognostic factors. All reported p-values were corrected using the permutation test (n = 100,000). Results: Four variants of rs881, rs17010730, rs727156, and rs3755462, as well as haplotypes containing the mentioned variants, were significantly associated with failure to achieve at least one of the defined efficacy endpoints. Variant annotation via in-silico studies revealed that the non-seed sequence variant, rs881, is located in the miRNA (hsa-miR-613) binding site. The other three variants or a variant in complete linkage disequilibrium with them overlap a region of high H3K9ac-promoter-like signature or regions of high enhancer-like signature in the brain or gastrointestinal tissue. Conclusion: Playing an essential role in regulating TACR1 expression, gene polymorphisms of TACR1 serve as the potential pharmacogenetic predictors of response to the NK-1 receptor antagonist-based, triple antiemetic regimens. If clinically approved, modifying the NK-1 receptor antagonist dose leads to better management of CINV in risk-allele carriers. [ABSTRACT FROM AUTHOR]

Achieving clinical effectiveness with vitamin K antagonists (VKAs) requires a Time in Therapeutic Range (TTR) above 65%. TTR is influenced by genetics (CYP2C9, VKORC1, CYP4F2), treatment adherence, and knowledge. The SAMe-TT2R2 algorithm is used to assess VKA treatment suitability. In this case report, SAMe-TT2R2 and pharmacogenetic analysis were used to improve oral anticoagulant management in a patient with poor control of INR. An 84-year-old, obese male with atrial fibrillation, undergoing acenocoumarol therapy, had a suboptimal TTR. An assessment with the SAMe-TT2R2 algorithm indicated a favorable profile for VKA use. An educational intervention on vitamin K-rich foods was conducted, and his physician was informed about the interaction between omeprazole and acenocoumarol, recommending its replacement with pantoprazole. This intervention was accepted by the physician and, three months post-intervention, the patient's TTR improved to 100%. Poor adherence and limited knowledge contributed to treatment failures in patients with a good VKA profile. Pharmaceutical interventions significantly improved TTR management. Patients with favorable genetic and clinical profiles could achieve adequate control of their anticoagulant medication through these interventions. Predictive tools may help select patients who can effectively and safely use VKAs through pharmaceutical interventions. [ABSTRACT FROM AUTHOR]

Mirabegron is a drug used in overactive bladder (OAB) treatment. Genetic variation in pharmacogenes might alter its pharmacokinetics, affecting its efficacy and safety. This research aimed to analyze the impact of genetic variation on mirabegron pharmacokinetics and safety. Volunteers from three bioequivalence trials (n = 79), treated with a single or a multiple dose of mirabegron 50 mg under fed or fasting conditions, were genotyped for 115 variants in pharmacogenes and their phenotypes were inferred. A statistical analysis was performed, searching for associations between genetics, pharmacokinetics and safety. CYP2D6 intermediate metabolizers showed a higher elimination half-life (t1/2) (univariate p-value (puv) = 0.018) and incidence of adverse reactions (ADRs) (puv = 0.008, multivariate p (pmv) = 0.010) than normal plus ultrarapid metabolizers. The UGT1A4 rs2011425 T/G genotype showed a higher t1/2 than the T/T genotype (puv = 0.002, pmv = 0.003). A lower dose/weight corrected area under the curve (AUC/DW) and higher clearance (CL/F) were observed in the SLC6A2 rs12708954 C/C genotype compared to the C/A genotype (puv = 0.015 and 0.016) and ADR incidence was higher when the SLCO1B1 function was decreased (puv = 0.007, pmv = 0.010). The lower elimination and higher ADR incidence when CYP2D6 activity is reduced suggest it might be a useful biomarker in mirabegron treatment. UGT1A4, SLC6A2 and SLCO1B1 might also be involved in mirabegron pharmacokinetics. [ABSTRACT FROM AUTHOR]

Gefitinib is a selective inhibitor of the epidermal growth factor receptor that is used to treat advanced and metastatic non-small cell lung cancer (NSCLC). Dermatological adverse reactions are most commonly associated with gefitinib treatment. The cause of adverse reactions in individuals is multifactorial. Pharmacogenetics is an effective tool to detect such adverse reactions. This case report describes a female patient with NSCLC who was administered gefitinib at a dose of 250 mg/day. However, due to severe adverse dermatological reactions, the treatment was interrupted for 15 d and antibiotic therapy was administered to manage the skin rashes, maculopapular rashes, and hyperpigmentation. Treatment adherence was adequate, and no drug interactions were detected. A pharmacogenetic analysis revealed homozygosity in the ATP-binding cassette (ABC)-B1 rs1128503 (c.1236A>G), heterozygosity in ABCG2 rs2231142 (c.421G>T) and rs2622604 (c.-20+614T>C), and a non-functional variant of the cytochrome P450 family 3, subfamily A, member 5 (CYP3A5). The relationship between altered genetic variants and the presence of adverse reactions induced by gefitinib is still controversial. Overall, this case report highlights the importance of continuing to study pharmacogenetics as predictors of adverse drug reactions. [ABSTRACT FROM AUTHOR]

To reduce severe fluoropyrimidine-related toxicity, pharmacogenetic guidelines recommend a dose reduction for carriers of four high-risk variants in the DPYD gene (*2A, *13, c.2846A>T, HapB3). The polymorphism in the MIR27A gene has been shown to enhance the predictive value of these variants. Our study aimed to explore whether rs895819 in the MIR27A gene modifies the effect of five common DPYD variants: c.1129-5923C>G (rs75017182, HapB3), c.2194G>A (rs1801160, *6), c.1601G>A (rs1801158, *4), c.496A>G (rs2297595), and c.85T>C (rs1801265, *9A). The study included 370 Caucasian patients with gastrointestinal tumors who received fluoropyrimidine-containing chemotherapy. Genotyping was performed using high-resolution melting analysis. The DPYD*6 allele was associated with overall severe toxicity and neutropenia with an increased risk particularly pronounced in patients carrying the MIR27A variant. All carriers of DPYD*6 exhibited an association with asthenia regardless of their MIR27A status. The increased risk of neutropenia in patients with c.496G was only evident in those co-carrying the MIR27A variant. DPYD*4 was also significantly linked to neutropenia risk in co-carriers of the MIR27A variant. Thus, we have demonstrated the predictive value of the *6, *4, and c.496G alleles of the DPYD gene, considering the modifying effect of the MIR27A polymorphism. [ABSTRACT FROM AUTHOR]

Purpose: Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are at high risk for severe and fatal toxicity from fluoropyrimidine (FP) chemotherapy. Pre-treatment DPYD testing is standard of care in many countries, but not the United States (US). This survey assessed pre-treatment DPYD testing approaches in the US to identify best practices for broader adoption. Methods: From August to October 2023, a 22-item QualtricsXM survey was sent to institutions and clinicians known to conduct pre-treatment DPYD testing and broadly distributed through relevant organizations and social networks. Responses were analyzed using descriptive analysis. Results: Responses from 24 unique US sites that have implemented pre-treatment DPYD testing or have a detailed implementation plan in place were analyzed. Only 33% of sites ordered DPYD testing for all FP-treated patients; at the remaining sites, patients were tested depending on disease characteristics or clinician preference. Almost 50% of sites depend on individual clinicians to remember to order testing without the assistance of electronic alerts or workflow reminders. DPYD testing was most often conducted by commercial laboratories that tested for at least the four or five DPYD variants considered clinically actionable. Approximately 90% of sites reported receiving results within 10 days of ordering. Conclusion: Implementing DPYD testing into routine clinical practice is feasible and requires a coordinated effort among the healthcare team. These results will be used to develop best practices for the clinical adoption of DPYD testing to prevent severe and fatal toxicity in cancer patients receiving FP chemotherapy. [ABSTRACT FROM AUTHOR]

Background: The study of genetic variation as a factor influencing drug safety, efficacy, and effectiveness has brought about significant breakthroughs in understanding the clinical application of gene-drug interactions to better manage drug therapy.Objective: This study was designed to assess the feasibility of collecting buccal samples by general practitioners (GPs) at private practices in Singapore within a usual consultation, incorporating use of a pharmacogenetics-based medical decision support system to guide subsequent drug dosing.Methods: We used a prospective cohort study design, with GPs recruiting 189 patients between October 2020 and March 2021. The genotypes of 51 biallelic SNPs were determined using Illumina Infinium Global Screening Array.Results: Seven GPs from 6 private practices recruited and obtained buccal samples from a total of 189 patients. All patients had at least one actionable variant. The prevalence of patients having 2, 3, or 4 variants was 37.0%, 32.8%, and 12.7%, respectively. Potential alterations to medications were identified using the Clinical Decision Support System. Patients were accepting and the GPs were enthusiastic about the potential of pharmacogenetics to personalize medicine for their patients.Conclusion: This is the first study in Singapore to demonstrate the feasibility of pharmacogenetic testing in primary care. The high prevalence of genetic variants underscores the potential use of pharmacogenetics in this setting. [ABSTRACT FROM AUTHOR]

Pharmacogenomics (PGx) results can potentially guide the prescribing of dozens of medications; however, use of such results is often limited by the prescriber's awareness of results and knowledge of drug–gene interactions. Integration of PGx results with corresponding clinical decision support (CDS) in the electronic health record (EHR) is critical to facilitate genotype‐guided medication prescribing among all clinicians in an integrated health system. We describe our experience with developing an infrastructure to house PGx results and ensure actionable findings can be used at the point of care in real time using CDS. Upon transitioning to a new EHR, PGx‐related CDS alerts for more than 50 medications were developed using a systematic and multidisciplinary process where clinical pharmacist input was key. Multiple strategies were required to enable the storage of PGx results as discrete data from any laboratory source to drive CDS. EHR features were leveraged to link results from external laboratories to CDS and a homegrown translational software platform was developed to integrate results from the in‐house genomics laboratory directly into the EHR. These processes enabled PGx result integration for 2342 patients. As an example, among 356 patients who were genotyped for CYP2C19 to guide voriconazole dosing as part of a standard protocol in bone marrow transplant, 114 (32%) had CDS alerts for medications other than voriconazole presented to a clinician. For 50 of these patients, alerts were presented to a clinician of a different specialty who likely was not aware the patient had PGx results. Clinical pharmacists at institutions performing PGx testing are encouraged to champion the integration of PGx results and CDS in the EHR to maximize clinician awareness and evidence‐based use of PGx results. [ABSTRACT FROM AUTHOR]

Introduction: Clopidogrel remains widely utilized in patients undergoing percutaneous coronary intervention despite compelling evidence that genetic variation impacts patient response to clopidogrel. Clinical decision support (CDS) is frequently used to aid in precision medicine; however, limitations within the electronic medical record can hinder reliable CDS. Procedural areas where standard order entry is not utilized create a barrier to CDS implementation. Objectives: We aimed to evaluate the implementation of a novel alerting mechanism on genotype‐guided antiplatelet prescribing within the cardiac catheterization laboratory procedural setting. Methods: A retrospective cohort study was conducted to assess the rate of antiplatelet ordering in patients with one or two loss‐of‐function cytochrome P450 2C19 (CYP2C19) alleles before and after alert implementation. Pharmacogenomic congruence was measured before and after the alert via chart abstraction that included the CYP2C19 genotype and antiplatelet medications ordered within that encounter. Results: A total of 236 patients were included in analyses, 127 encounters within the cohort before alert implementation and 136 encounters in the cohort after alert implementation. Prior to alert implementation, 40.9% (n = 127) were prescribed clopidogrel compared with 25.7% (n = 136) post implementation. After implementing a genotype‐guided alert within the cardiac catheterization laboratory procedural setting, providers were 2.22 times more likely to prescribe an alternative antiplatelet (p = 0.024). Clopidogrel‐naïve patients were 9.75 times more likely to receive a genotype‐guided antiplatelet order following alert implementation (p < 0.05). Conclusion: Providers were responsive to a novel alert within the cardiac catheterization laboratory procedural setting. Genotype‐guided antiplatelet prescribing significantly increased following the alert implementation. [ABSTRACT FROM AUTHOR]

Background: Human immunodeficiency virus (HIV) and tuberculosis (TB) are major contributors to morbidity and mortality in sub-Saharan Africa including Cameroon. Pharmacogenetic variants could serve as predictors of drug-induced hepatotoxicity (DIH), in patients with TB co-infected with HIV. We evaluated the occurrence of DIH and pharmacogenetic variants in Cameroonian patients. Methods: Treatment-naïve patients with HIV, TB or TB/HIV co-infection were recruited at three hospitals in Cameroon, between September 2018 and November 2019. Appropriate treatment was initiated, and patients followed up for 12 weeks to assess DIH. Pharmacogenetic variants were assessed by allele discrimination TaqMan SNP assays. Results: Of the 141 treatment naïve patients, the overall incidence of DIH was 38% (53/141). The highest incidence of DIH, 52% (32/61), was observed among HIV patients. Of 32 pharmacogenetic variants, the slow acetylation variants NAT2*5 was associated with a decreased risk of DIH (OR: 0.4; 95%CI: 0.17–0.96; p = 0.038), while NAT2*6 was found to be associated with an increased risk of DIH (OR: 4.2; 95%CI: 1.1–15.2; p = 0.017) among patients treated for TB. Up to 15 SNPs differed in ≥ 5% of allele frequencies among African populations, while 25 SNPs differed in ≥ 5% of the allele frequencies among non-African populations, respectively. Conclusions: DIH is an important clinical problem in African patients with TB and HIV. The NAT2*5 and NAT2*6 variants were found to be associated with DIH in the Cameroonian population. Prior screening for the slow acetylation variants NAT2*5 and NAT2*6 may prevent DIH in TB and HIV-coinfected patients. [ABSTRACT FROM AUTHOR]

Pharmacogenetics investigates sequence of genes that affect drug response, enabling personalized medication. This approach reduces drug-induced adverse reactions and improves clinical effectiveness, making it a crucial consideration for personalized medical care. Numerous guidelines, drawn by global consortia and scientific organizations, codify genotype-driven administration for over 120 active substances. As the scientific community acknowledges the benefits of genotype-tailored therapy over traditionally agnostic drug administration, the push for its implementation into Italian healthcare system is gaining momentum. This evolution is influenced by several factors, including the improved access to patient genotypes, the sequencing costs decrease, the growing of large-scale genetic studies, the rising popularity of direct-to-consumer pharmacogenetic tests, and the continuous improvement of pharmacogenetic guidelines. Since EMA (European Medicines Agency) and AIFA (Italian Medicines Agency) provide genotype information on drug leaflet without clear and explicit clinical indications for gene testing, the regulation of pharmacogenetic testing is a pressing matter in Italy. In this manuscript, we have reviewed how to overcome the obstacles in implementing pharmacogenetic testing in the clinical practice of the Italian healthcare system. Our particular emphasis has been on germline testing, given the absence of well-defined national directives in contrast to somatic pharmacogenetics. [ABSTRACT FROM AUTHOR]

Background Objectives Materials and methods Results Conclusions Cardiovascular disease induces erectile dysfunction modulated by endothelial nitric oxide synthase enzyme and an impaired ejection fraction that restricts penis vascular congestion. However, the mechanisms regulating endothelial dysfunction are not understood.Exploring the functional impact of endothelial nitric oxide synthase genetic polymorphisms on erectile dysfunction and drug therapy optimization in high‐risk cardiovascular disease patients.Patients with erectile dysfunction symptoms and candidates for andrology therapy were included (n = 112). Clinical data and endothelial nitric oxide synthase rs1799983 (G894T) and rs2070744 (T‐786C), genotyped by fluorescence polarization assays, were registered. The 27‐bp variable number of the tandem repeat polymorphism in intron 4 (intron4b/a) was analyzed by polymerase chain reaction‐restriction fragment length polymorphism. Association analyses were run with the R‐3.2.0 software.A significant association between endothelial nitric oxide synthase 786‐TT (p = 0.005) and the aa/ac of intron 4 variable number of the tandem repeat (p = 0.02) with higher erectile dysfunction susceptibility was observed in cardiovascular disease patients (60 ± 9 years, 66% severe erectile dysfunction, 56% ejection fraction). After 3‐months of phosphodiesterase type 5 inhibitors, erectile dysfunction (International Index of Erectile Function, 50 ± 16 scores, the International Index of Erectile Function‐Erectile Function 21 ± 10 scores, p < 0.001) and sexual quality of life (modified Sexual Life Quality Questionnaire 55 ± 23 scores, p < 0.001) had significantly improved. The cardiovascular ejection fraction was influenced positively with better sexual quality of life (0.1941), and also in the endothelial nitric oxide synthase G894‐T allele (p = 0.076) carriers, which could merit future analyses. Erectile dysfunction was present as the primary clinical manifestation in 62% of cases, with cardiovascular disease occurring concurrently. Only former smokers and obese subjects debuted prior to cardiovascular disease than to erectile dysfunction.Our study provides comprehensive insights into the functional interaction linking endothelial nitric oxide synthase gene polymorphisms, erectile function, and ejection fraction in high‐risk cardiovascular disease patients. Future therapeutic strategies could target endothelial nitric oxide synthase activity by including lifestyle changes and epigenetic modulations. [ABSTRACT FROM AUTHOR]

Aims: Genetic testing can be used to improve the safety and effectiveness of commonly prescribed medicines—a concept known as pharmacogenetics. This study aimed to quantify members of the UK public's preferences for a pharmacogenetic service to be delivered in primary care in the National Health Service. Methods: Members of the UK population were surveyed via an online panel company. Respondents completed 1 of 2 survey versions, asking respondents to select their preferred pharmacogenetic testing service in the context of a presentation of low mood or pain. A conditional logit model was estimated, before the best functional form for the dataset was identified. Preference heterogeneity was identified via latent class analysis. Coefficients from the final selected models were used to estimate uptake in the context of different hypothetical pharmacogenetic services. Results: Responses from 1993 individuals were included in the analysis. There were no differences observed in preference between the 2 clinical scenarios. Conditional logit analysis, using maximum likelihood estimation, indicated that respondents preferred to have noninvasive tests and wanted their data to be shared between different healthcare organizations to guide future prescribing. There was a preference for regional over national data sharing initiatives, and respondents preferred to have access to their data. Predicted uptake varied considerably, ranging from 51% to >99%, depending on design of the service. Conclusion: This study identifies public preferences for a pharmacogenetic testing service and demonstrates how predicted uptake can be impacted by relatively minor adaptations. This highlights areas for prioritization during development of future pharmacogenetic services. [ABSTRACT FROM AUTHOR]

Background Approximately 15–25% of depressed patients suffer from difficult-to-treat depression (DTD). Patients with DTD require a thorough examination to avoid the oversight of treatable (psychiatric/somatic) comorbidities or (pseudo-)resistance to antidepressant drugs (ADs). Polymorphisms of the cytochrome P450 (CYP) enzymes 2D6 and 2C19, which play a major role in the metabolism of ADs, may contribute to resistance to ADs. Patients with DTD might benefit from electroconvulsive therapy (ECT). Methods We enrolled 109 patients with DTD and 29 untreated depressed controls (UDC). We assessed risk phenotypes, comorbidities, and treatment, including ECT. We also performed pharmacokinetic analyses of CYP2D6 and CYP2C19. Results DTD patients significantly more often suffered from comorbid psychiatric diseases, especially ICD-10: F40-F48 (DTD:40.4%, UDC:17.2%, OR 11.87, p =0.011) than UDC patients. DTD patients receiving ECT were more likely to achieve remission (37.7% vs. 11.8%, OR=3.96, p =0.023). Treatment with ADs did not differ between remitters and non-remitters. No significant differences were observed in the distribution of CYP2D6 and CYP2C19 variants between both groups. Conclusion Patients with DTD appear to experience comorbid neurotic stress and somatoform disorders (ICD-10: F40 – F48) more frequently. Therefore, a comprehensive differential diagnosis is crucial when patients do not respond sufficiently to antidepressant medication. Genotyping CYP2D6 and CYP2C19 should be considered. [ABSTRACT FROM AUTHOR]

Fluoropyrimidines (FPs) are commonly prescribed in many cancer streams. The EMA and FDA-approved drug labels for FPs recommend genotyping the DPYD*2A (rs3918290), *13 (rs55886062), *HapB3 (rs56038477), alleles, and DPYD rs67376798 before treatment starts. We implemented the DPYD genotyping in our daily clinical routine, but we still found patients showing severe adverse drug events (ADEs) to FPs. We studied among these patients the DPYD rs1801265, rs17376848, rs1801159, rs1801160, rs1801158, and rs2297595 as explanatory candidates of the interindividual differences for FP-related toxicities, examining the association with the response to FPs. We also studied the impact of DPYD testing for FP dose tailoring in our clinical practice and characterized the DPYD gene in our population. We found a total acceptance among physicians of therapeutic recommendations translated from the DPYD test, and this dose tailoring does not affect the treatment efficacy. We also found that the DPYD*4 (defined by rs1801158) allele is associated with a higher risk of ADEs (severity grade ≥ 3) in both the univariate (O.R. = 5.66; 95% C.I. = 1.35–23.67; p = 0.014) and multivariate analyses (O.R. = 5.73; 95% C.I. = 1.41–28.77; p = 0.019) among FP-treated patients based on the DPYD genotype. This makes it a candidate variant for implementation in clinical practice. [ABSTRACT FROM AUTHOR]

The human N-acetyltransferase 2 enzyme, encoded by the NAT2 gene, plays an important role in the metabolism of isoniazid, the main drug used to treat tuberculosis. The interindividual variation in the response of patients to drug treatment for tuberculosis may be responsible for the occurrence of unfavorable outcomes. The presence of polymorphisms in genes associated with the metabolism and transport of drugs, receptors, and therapeutic targets has been identified as a major determinant of this variability. The objective of this study was to identify the genetic profile of NAT2 in the study population. Using the obtained genomic DNA followed by PCR amplification and sequencing, the frequency of nine SNPs as well as alleles associated with slow (47.9%), intermediate (38.7%), and fast acetylation phenotypes (11.3%), in addition to those whose phenotype has not yet been characterized (2.1%), was estimated. The NAT2*5B allele was identified more frequently (31.3%). The description of SNPs in pharmacogenes and the establishment of their relationship with the pharmacokinetics of an individual offer an individualized approach that allows us to reduce the unfavorable outcomes of a therapy, ensure better adherence to treatment, prevent the emergence of MDR strains, reduce the cost of treatment, and improve the quality of patients' lives. [ABSTRACT FROM AUTHOR]

Opioid use disorder (OUD) is a multifaceted condition influenced by sex, genetic and environmental factors that could be linked with epigenetic changes. Understanding how these factors interact is crucial to understand and address the development and progression of this disorder. Our aim was to elucidate different potential epigenetic and genetic mechanisms between women and men that correlate with OUD under real‐world pain unit conditions. Associations between analgesic response and the DNA methylation level of the opioid mu receptor (OPRM1) gene (CpG sites 1–5 selected in the promoter region) were evaluated in 345 long opioid‐treated chronic non cancer pain: cases with OUD (n = 67) and controls (without OUD, n = 278). Cases showed younger ages, low employment status and quality of life, but higher morphine equivalent daily dose and psychotropic use, compared to the controls. The patients with OUD showed a significant decrease in OPRM1 DNA methylation, which correlated with clinical outcomes like pain relief, depression and different adverse events. Significant differences were found at the five CpG sites studied for men, and exclusively in women for CpG site 3, in relation to OUD diagnosis. These findings support the importance of epigenetics and sex as biological variables to be considered toward efficient OUD understanding and therapy development. [ABSTRACT FROM AUTHOR]

Objectives: The pathology of Tardive Dyskinesia (TD) has yet to be fully understood, but there have been proposed hypotheses for the cause of this condition. Our team previously reported a possible association of TD with the Complement Component C4 gene in the HLA region. In this study, we explored the HLA region further by examining two previously identified schizophrenia‐associated HLA‐region single‐nucleotide polymorphisms (SNPs), namely rs13194504 and rs210133. Methods: The SNPs rs13194504 and rs210133 were tested for association with the occurrence and severity of TD in a sample of 172 schizophrenia patients who were recruited for four studies from three different clinical sites in Canada and USA. Results: The rs13194504 AA genotype was associated with decreased severity for TD as measured by Abnormal Involuntary Movement Scale (AIMS) scores (p = 0.047) but not for TD occurrence. SNP rs210133 was not significantly associated with either TD occurrence or AIMS scores. Conclusion: Our findings suggest that the rs13194504 AA genotype may play a role in TD severity, while SNP rs210133 may not have a major role in the risk or severity of TD. [ABSTRACT FROM AUTHOR]

Background: Guided by Clinical Pharmacogenomic Implementation Consortium(CPIC) guidelines for >140medications, pharmacogenomic tests inform medication selection and dosing to optimize efficacy while minimizing toxicities. Purpose: This study assessed pharmacogenomic self-reported curricular content, knowledge, skills, attitudes, and usage in advanced practice registered nurses (APRNs) with prescriptive privileges. Methodology: An online survey was administered assessing pharmacogenomic curricular content, knowledge, skills, attitudes, and usage. Results: Data from 266 APRNs were analyzed. Most graduated with their highest nursing degree; 10 years ago and reported pharmacogenomic curricular content (n = 124, 48%). Pharmacogenomic curricular content was associated with pharmacogenomic familiarity (p = .045) but not with knowledge confidence (p = .615). Pharmacogenomic usage, defined as ordering a pharmacogenomic test within the past year, was low (n = 76, 29%) and most (n = 210, 84%) reported never using CPIC Guidelines. Advanced practice registered nurses (n = 162) who did not anticipate ordering a pharmacogenomic test in the next year (n = 77, 48%) indicated that they did not know what test to order. Conclusions: Deficits were identified in APRN pharmacogenomic knowledge and skills despite academic training. Most reported not ordering pharmacogenomic tests, did not know what test to order, and did not use CPIC guidelines. Implications: Pharmacogenomics is a quality and safety issue. Academic training did not result in practice integration and most reported capacity deficits. Recommendation for overcoming academic deficits include: (1) assessment of pharmacogenomics curricular content and faculty teaching capacity; (2) training addressing identified deficiencies; and (3) Commission of Collegiate Nursing Education policies that include pharmacogenomics in advanced pharmacology. Practicing APRN plans include on-the-job training and/or mandatory training at the time of relicensure. [ABSTRACT FROM AUTHOR]

There is growing evidence that pharmacogenetic analysis can improve drug therapy for individual patients. In Switzerland, pharmacists are legally authorized to initiate pharmacogenetic tests. However, pharmacogenetic tests are rarely conducted in Swiss pharmacies. Therefore, we aimed to identify implementation strategies that facilitate the integration of a pharmacist-led pharmacogenetic service into clinical practice. To achieve this, we conducted semi-structured interviews with pharmacists and physicians regarding the implementation process of a pharmacist-led pharmacogenetic service. We utilized the Consolidated Framework for Implementation Research (CFIR) to identify potential facilitators and barriers in the implementation process. Additionally, we employed Expert Recommendations for Implementing Change (ERIC) to identify strategies mentioned in the interviews and used the CFIR-ERIC matching tool to identify additional strategies. We obtained interview responses from nine pharmacists and nine physicians. From these responses, we identified 7 CFIR constructs as facilitators and 12 as barriers. Some of the most commonly mentioned barriers included unclear procedures, lack of cost coverage by health care insurance, insufficient pharmacogenetics knowledge, lack of interprofessional collaboration, communication with the patient, and inadequate e-health technologies. Additionally, we identified 23 implementation strategies mentioned by interviewees using ERIC and 45 potential strategies using the CFIR-ERIC matching tool. In summary, we found that significant barriers hinder the implementation process of this new service. We hope that by highlighting potential implementation strategies, we can advance the integration of a pharmacist-led pharmacogenetic service in Switzerland. [ABSTRACT FROM AUTHOR]

Growth and maturation characterize the transition of neonates to adults. The physiological changes that children undergo present numerous pharmacological conundrums for the anaesthetist. Extensive changes in drug absorption, protein binding, metabolism and excretion during development result in wide variability in drug disposition. Pharmacodynamic differences and genetic polymorphisms further exacerbate these pharmacokinetic disparities. These changes directly affect drug efficacy and toxicity, and an awareness of this is crucial for clinicians involved in paediatric anaesthesia. Population-based pharmacokinetic–pharmacodynamic modelling provides a novel prospect in paediatric pharmacology research. Modelling has the potential to improve safety in clinical trials and enhance our understanding of drug disposition in vulnerable populations like preterm neonates. Although progress is occurring in developmental pharmacology, gaps remain, and a lot yet remains to be elucidated. [ABSTRACT FROM AUTHOR]

Background: Allelic variants of genes encoding enzymes of the esterase system (CES1) and P-glycoprotein (ABCB1) can change the metabolism and pharmacokinetics of dabigatran. Therefore, they act as determining factors in the development of side effects, especially bleeding. We analyzed the genotype--phenotype relationship of ABCB1 (rs1045642, rs4148738, rs2032582, and rs1128503) and CES1 (rs8192935, rs71647871, and rs2244613) polymorphisms in patients with atrial fibrillation who had been treated with dabigatran. Methods: A total of 150 patients were recruited for this study. TaqMan technology was used for SNP genotyping. Results: Patients with the rs2244613 GG genotype had a lower concentration (55.27 ± 34.22 ng/ml) compared to those with the TT genotype (63.33 ± 52.25 ng/ml) (additive model, P = 0.000). Individuals with the rs8192935 AA genotype had a lower concentration (52.72 ± 30.45 ng/ml) compared to those with the GG genotype (79.78 ± 57 ng/ml) (additive model, P = 0.001). The APTT values among the different genotypes of the ABCB1 SNPs, rs4148738 and rs1045642, were significantly different (P = 0.035 and P = 0.024, respectively). Conclusion: Our research demonstrates that the CES1 polymorphisms, rs8192935 and rs2244613, are associated with the pharmacodynamics and pharmacokinetics of dabigatran in the Kazakh subpopulation. [ABSTRACT FROM AUTHOR]

Purpose To describe our experiences implementing and iterating CYP2C19 genotype–guided clopidogrel pharmacogenetic clinical decision support (CDS) tools over time in the setting of a large health system–wide, preemptive pharmacogenomics program. Summary Clopidogrel-treated patients who are genetically predicted cytochrome P450 isozyme 2C19 (CYP2C19) intermediate or poor metabolizers have an increased risk of atherothrombotic events, some of which can be life-threatening. The Clinical Pharmacogenetics Implementation Consortium provides guidance for the use of clopidogrel based on CYP2C19 genotype in patients with cardiovascular and cerebrovascular diseases. Our multidisciplinary team implemented an automated, interruptive alert that fires when clopidogrel is ordered or refilled for biobank participants with structured CYP2C19 intermediate or poor metabolizer genomic indicators in the electronic health record. The implementation began with a narrow cardiovascular indication and setting and was then scaled in 4 primary dimensions: (1) clinical indication; (2) availability across health-system locations; (3) care venue (e.g. inpatient vs outpatient); and (4) provider groups (eg, cardiology and neurology). We iterated our approach over time based on evolving clinical evidence and proactive strategies to optimize CDS maintenance and sustainability. A key facilitator of expansion was socialization of the broader pharmacogenomics initiative among our academic medical center community, accompanied by clinician acceptance of pharmacogenetic alerts in practice. Conclusion A multidisciplinary collaboration is recommended to facilitate the use of CYP2C19 genotype–guided antiplatelet therapy in patients with cardiovascular and cerebrovascular diseases. Evolving clopidogrel pharmacogenetic evidence necessitates thoughtful iteration of implementation efforts and strategies to optimize long-term maintenance and sustainability. [ABSTRACT FROM AUTHOR]

Background: Antipsychotics, including risperidone (RIS), are frequently indicated for various autism spectrum disorder (ASD) manifestations; however, "actionable" PGx testing in psychiatry regarding antipsychotic dosing and selection has limited applications in routine clinical practice because of the lack of standard guidelines, mostly due to the inconsistency and scarcity of genetic variant data. The current study is aimed at examining the association of RIS effectiveness, according to ABC-CV and CGI indexes, with relevant pharmacokinetics (PK) and pharmacodynamics (PD) genes. Methods: Eighty-nine ASD children who received a consistent RIS-based regimen for at least 8 weeks were included. The Axiom PharmacoFocus Array technique was employed to generate accurate star allele-predicted phenotypes of 3 PK genes (CYP3A4, CYP3A5, and CYP2D6). Genotype calls for 5 candidate PD receptor genes (DRD1, DRD2, DRD3, HTR2C, and HTR2A) were obtained and reported as wild type, heterozygous, or homozygous for 11 variants. Results: Based on the ABC total score, 42 (47.2%) children were classified as responders, while 47 (52.8%) were classified as nonresponders. Multivariate logistic regression analyses, adjusted for nongenetic factors, suggested nonsignificant impacts of the star allele-predicted phenotypes of all 3 PK genes on improvement in ASD symptoms or CGI scores. However, significant positive or negative associations of certain PD variants involved in dopaminergic and serotonergic pathways were observed with specific ASD core and noncore symptom subdomains. Our significant polymorphism findings, mainly those in DRD2 (rs1800497, rs1799978, and rs2734841), HTR2C (rs3813929), and HTR2A (rs6311), were largely consistent with earlier findings (predictors of RIS effectiveness in adult schizophrenia patients), confirming their validity for identifying ASD children with a greater likelihood of core symptom improvement compared to noncarriers/wild types. Other novel findings of this study, such as significant improvements in DRD3 rs167771 carriers, particularly in ABC total and lethargy/social withdrawal scores, and DRD1 rs1875964 homozygotes and DRD2 rs1079598 wild types in stereotypic behavior, warrant further verification in biochemical and clinical studies to confirm their feasibility for inclusion in a PGx panel. Conclusion: In conclusion, we provide evidence of potential genetic markers involved in clinical response variability to RIS therapy in ASD children. However, replication in prospective samples with greater ethnic diversity and sample sizes is necessary. [ABSTRACT FROM AUTHOR]