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Background: Cytochrome P450 is a superfamily of genes generating hemoproteins that metabolize foreign chemicals as well as endogenous compounds, such as steroids. The human CYP2C genes (CYP2C8, CYP2C9, CYP2C18, CYP2C19) cluster on chromosome 10 and metabolize many clinically useful drugs. CYP2C19 and CYP2C9 have been the most studied while CYP2C8 has been studied less frequently. CYP2C18 has been relatively ignored until recently but its importance has begun to be recognized. Methods and results: We studied the genotypes of 7 pharmacogenetic markers in 3 CYP2C genes: CYP2C19 (rs12248560), CYP2C9 (rs4918758, rs1799853), and CYP2C8 (rs10509681, rs11572103, rs1058930, rs11572080), in one Libyan population and 7 Tunisian populations. Five of the 7 SNPs are in exons and have functional consequences while one intronic SNP is considered to be in close proximity to a regulatory region because of the many studies that report associations with metabolic effects. We carried out principal component analysis (PCA) on the North African populations and 83 other populations from the 1000 Genomes Project and Kidd Laboratory. The geographic clustering observed via PCA was more pronounced when considering multi-SNP haplotype frequencies. Conclusion: This study reveals the intermediate position of North Africans between Europeans and Asians and the varied dissimilarities with other world regions. The genetic variation observed within and between geographic regions have implications for drug metabolism and adverse individual responses to medical treatments. [ABSTRACT FROM AUTHOR]

Objective: Cytochrome P450 2C19 (CYP2C19) plays an vital role in the course of cardiovascular and cerebrovascular diseases by affecting lipid metabolism. Triglyceride-glucose (TyG) is a comprehensive index composed of triglyceride and blood glucose, has relationship with some diseases. There was no research report on the association CYP2C19 polymorphisms, TyG with premature cerebral infarction (CI) (onset ≤ 65 years old) susceptibility. Methods: This study retrospectively analyzed 1953 CI patients aged ≤ 65 years old from December 2018 to March 2024, and 1919 age-matched individuals with non-CI as controls. The relationship between CYP2C19 polymorphisms, TyG and premature CI risk were analyzed. Results: The proportion of hypertension, and diabetes mellitus in patients with premature CI was higher than those in controls. The serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein-cholesterol (LDL-C), and TyG levels in patients with premature CI were significantly higher than those in controls (all p < 0.05). The patients had lower CYP2C19 *1 allele frequency (63.3% vs. 69.6%, p < 0.001) and higher CYP2C19 *2 allele frequency (31.3% vs. 25.4%, p < 0.001) than controls. Logistic regression analysis showed that smoking history (odds ratio (OR): 1.193, 95% confidence interval (CI): 1.002–1.422, p = 0.048), hypertension (OR: 3.371, 95% CI: 2.914–3.898, p < 0.001), diabetes mellitus (OR: 1.911, 95% CI: 1.632–2.237, p < 0.001), CYP2C19 intermediate metabolizer (IM) + poor metabolizer (PM) phenotypes (OR: 1.424, 95% CI: 1.243–1.631, p < 0.001), and dyslipidemia (OR: 1.294, 95% CI: 1.077–1.554, p = 0.006) were independent risk factors for premature CI. Conclusions: History of smoking, hypertension, diabetes mellitus, dyslipidemia, and CYP2C19 IM + PM phenotypes were independently associated with premature CI susceptibility. [ABSTRACT FROM AUTHOR]

Introduction: Pharmacogenetics (PGx) holds promise for optimizing psychotropic medication use, with CYP2D6 and CYP2C19 identified as key genes in antidepressant treatment. However, few studies have explored the genetic variants of these genes in real-world settings for patients experiencing ineffectiveness or adverse drug reactions (ADRs) to antidepressants. Methods: This case series includes 40 patients who underwent PGx testing due to antidepressant ineffectiveness or ADRs between June 2020 and April 2022. We describe the patients' demographic, clinical, and genetic characteristics and assess the value of PGx testing based on feedback from their psychiatrists. Results: The most common diagnoses were major depressive disorder (60.0%) and post-traumatic stress disorder (30.0%). Ineffectiveness was reported in 65.0% of patients, ADRs in 2.5%, and both in 32.5%. The antidepressants involved included SSRIs (45.0%), SNRIs (27.5%), atypical antidepressants (20.0%), and tricyclics (17.5%). Only 17.5% of patients had normal CYP2D6 and CYP2C19 metabolic activity. Actionable genetic variants were identified in 22.0% of CYP2D6/CYP2C19-antidepressant-response pairs. PGx recommendations were followed in 92.7% of cases, with significant improvement in ADRs reported in 71.4% of patients and efficacy improvement in 79.5%. Discussion: Our findings suggest that PGx testing can guide prescribing decisions for patients with antidepressant ineffectiveness or ADRs. The relatively high prevalence of genetic variants affecting pharmacokinetics supports the broader adoption of PGx testing in psychiatric practice. [ABSTRACT FROM AUTHOR]

Omeprazole (OME) is a CYP2C19 phenotyping probe, marketed as a racemic (S)/(R) mixture or as an S‐enantiomer. Both CYP2C19 and CYP3A4 enzymes mediate (R)‐OME hydroxylation to (R)‐5‐hydroxyomeprazole, while (S)‐OME is exclusively hydroxylated via CYP2C19. This study investigates OME and its 5‐hydroxymetabolite enantiomers' pharmacokinetics using data from two studies involving healthy volunteers. In Study A, volunteers received OME alone in Session 1, OME combined with voriconazole and fluvoxamine in Session 2 and finally OME with rifampicin in Session 3. In Study B, volunteers received OME alone in Session 1, OME combined with voriconazole in Session 2 and finally OME with fluvoxamine in Session 3. Despite low metabolic ratio values of (S)‐OME, detectable modulation of CYP2C19 activity suggests both (R)‐ and (S)‐OME isomers could effectively assess CYP2C19 activity. Further research is needed for precise cut‐offs in different phenotype groups. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications DT‐678 is a novel antiplatelet prodrug, capable of releasing the antiplatelet active metabolite of clopidogrel (AM) upon exposure to glutathione. In this study, we investigated factors responsible for clopidogrel high on‐treatment platelet reactivity (HTPR) in acute coronary syndrome (ACS) patients and evaluated the capacity of DT‐678 to overcome HTPR.A total of 300 consecutive ACS patients naive to P2Y12 receptor inhibitors were recruited and genotyped for CYP2C19 alleles. Blood samples were drawn before and after administration of 600‐mg clopidogrel. Platelet reactivity index (PRI) and plasma AM concentrations were determined and grouped according to their CYP2C19 genotypes. DT‐678 was applied ex vivo to whole blood samples to examine its inhibitory effects. To further examine the antiplatelet effectiveness of DT‐678 in vivo, 20 healthy human subjects were recruited in a Phase I clinical trial, and each received a single dose of either 3‐mg DT‐678 or 75‐mg clopidogrel. The pharmacokinetics and pharmacodynamics in different CYP2C19 genotype groups were compared.Statistical analyses revealed that CYP2C19 genotype, body mass index, hyperuricaemia, and baseline PRI were significantly associated with a higher risk of clopidogrel HTPR in ACS patients. The addition of DT‐678 ex vivo decreased baseline PRI regardless of CYP2C19 genotypes, overcoming clopidogrel HTPR. This observation was further confirmed in healthy volunteers receiving 3 mg of DT‐678.These results suggest that DT‐678 effectively overcomes clopidogrel HTPR resulting from genetic and/or clinical factors in Chinese ACS patients, demonstrating its potential to improve antiplatelet therapy. [ABSTRACT FROM AUTHOR]

Abrocitinib is a selective Janus kinase 1 inhibitor approved for the treatment of atopic dermatitis. It is metabolized primarily by cytochrome P450 (CYP) 2C19 (approximately 53%) and CYP2C9 (approximately 30%), which form 2 active metabolites. The pharmacologic activity of abrocitinib is attributable to the unbound exposures of abrocitinib and those metabolites with active moiety area under the plasma concentration–time curve (AUC) considered the best measure of the total pharmacological effect. The effect of CYP2C19 and/or CYP2C9 genotypes on abrocitinib and active moiety exposures were evaluated using a meta‐analysis of the noncompartmental estimates of exposure pooled from 10 clinical studies. A linear mixed‐effects model was developed on the basis of the power model to evaluate the effect of CYP2C19 and/or CYP2C9 genotypes on exposure (i.e., abrocitinib AUC and peak plasma concentration, active moiety AUC and peak plasma concentration). The genotypes were evaluated individually and as a combined phenotype effect. When evaluating the poor metabolizers of CYP2C19 or CYP2C9 individually, the estimated increases were 44.9% and 42.0% in active moiety AUC, respectively. The combined phenotype models showed a 0.6% decrease, and 25.1% and 10.5% increases in the active moiety AUC for "elevated," "mixed," and "reduced" metabolizers, respectively. Overall, the active moiety exposures did not appear to be affected to a clinically meaningful extent by different genotypes of CYP2C19 and/or CYP2C9. [ABSTRACT FROM AUTHOR]

This study aimed to characterize the population pharmacokinetics of sertraline in Mexican patients with psychiatric and substance use disorders. Fifty‐nine patients (13 to 76 years old) treated with doses of sertraline between 12.5 and 100 mg/day were included. Plasma sertraline concentrations were determined in blood samples and five of the main substances of abuse were determined by rapid tests in urine samples. Demographic, clinical, and pharmacogenetic factors were also evaluated. Population pharmacokinetic analysis was performed using NONMEM software with first‐order conditional estimation method. A one‐compartment model with proportional residual error adequately described the sertraline concentrations versus time. CYP2D6*2 polymorphism and CYP2C19 phenotypes significantly influenced sertraline clearance, which had a population mean value of 66 L/h in the final model. The absorption constant and volume of distribution were fixed at 0.855 1/h and 20.2 L/kg, respectively. The model explained 11.3% of the interindividual variability in sertraline clearance. The presence of the CYP2D6*2 polymorphism caused a 23.1% decrease in sertraline clearance, whereas patients with intermediate and poor phenotype of CYP2C19 showed 19.06% and 48.26% decreases in sertraline clearance, respectively. The model was internally validated by bootstrap and visual predictive check. Finally, stochastic simulations were performed to propose dosing regimens to achieve therapeutic levels that contribute to improving treatment response. [ABSTRACT FROM AUTHOR]

Aims: The aim of the present study was to investigate the impact of CYP2D6 genotype on exposure and metabolism of escitalopram in patients stratified by CYP2C19 genotype in a large real‐world population. Methods: Patients were included from a therapeutic drug monitoring service if they had measured serum concentration of escitalopram and the metabolite, N‐desmethyl escitalopram, and performed CYP2C19 and CYP2D6 genotyping. Patients were divided into 16 combined genotype‐predicted phenotype subgroups (poor [PM], intermediate [IM], normal [NM] and ultrarapid metabolizers [UM]) of CYP2C19/CYP2D6. The concentration‐to‐dose (CD) ratio and metabolite‐to‐parent ratio (metabolic ratio) of escitalopram were compared across subgroups using the Kruskal–Wallis test followed by Dunn's test with CYP2D6 NMs as the reference group. Results: A total of 5067 patients were included in the study. A stepwise increase in escitalopram CD ratio by decreasing CYP2D6 activity was observed in all CYP2C19 subgroups, except for in CYP2C19 UMs. The percentage differences in escitalopram CD ratio between CYP2D6 PMs and NMs were 24% in CYP2C19 NMs (P <.001), 28% in CYP2C19 IMs (P <.001) and 31% in CYP2C19 PMs (P =.04). As for the CD ratio, CYP2D6 genotype effect on metabolic ratio increased stepwise by decreasing CYP2C19 metabolism. Conclusions: CYP2D6 genotype is of significant importance for the individual variation in escitalopram pharmacokinetics. The most relevant increase in escitalopram concentration is seen in individuals with decreased and/or absent CYP2C19 activity. By combining CYP2C19 and CYP2D6 genotypes, the optimal dose for patients may be predicted with greater precision than for CYP2C19 genotype alone. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Cardiovascular events prognosis based on CYP2C19 gene polymorphisms had many applications in clinical practice. Assessed characteristics and predictive performance of cardiovascular events in acute coronary syndrome patients with CYP2C19 gene polymorphisms. PATIENTS AND METHODS: The patients were analyzed for CYP2C19 gene polymorphisms by real-time polymerase chain reaction (PCR). The PCR worked with primers around the mutant, as well as two fluorescent probes, one specific for the normal allele and the other for the mutant allele, and cardiovascular events were followed at 3 months and 6 months. RESULTS: Patients with CYP2C19 gene polymorphism accounted for 48.6% of which CYP2C19 *1/*2 genotype had the highest proportion (31.7%). The normal metabolizer phenotype was the majority (51.4%), and the *1 allele proportion accounted for the most (72.2%). Patients with type 2 diabetes (HR: 3.082, 95% CI: 1.652-5.747, p < 0.001) and ST-segment elevation myocardial infarction (HR: 2.874, 95% CI: 1.528-5.404, p = 0.001) were independent prognostic factors for cardiovascular events at 90 days. Type 2 diabetes was an independent prognostic factor for cardiovascular events at 180 days (HR: 3.714, 95% CI: 1.557-8.862, p = 0.003). The CYP2C19 gene polymorphism was an independent prognostic factor of cardiovascular events at 90 days (HR: 1.965, 95% CI: 1.012-3.814, p = 0.046). However, at 180 days of analysis, the association between the CYP2C19 gene polymorphism was not significant (HR: 2.234, 95% CI: 0.862-5.789, p = 0.098). CONCLUSIONS: CYP2C19 gene polymorphism was an independent prognostic factor of cardiovascular events 90 days after acute coronary syndrome. [ABSTRACT FROM AUTHOR]

The CYP2C19 enzyme metabolizes clopidogrel, a prodrug, to its active form. Approximately 30% of individuals inherit a loss-of-function (LoF) polymorphism in the CYP2C19 gene, leading to reduced formation of the active clopidogrel metabolite. Reduced clopidogrel effectiveness has been well documented in patients with an LoF allele following an acute coronary syndrome or percutaneous coronary intervention. Prasugrel or ticagrelor is recommended in those with an LoF allele as neither is affected by CYP2C19 genotype. Although data demonstrate improved outcomes with a CYP2C19 -guided approach to P2Y 12 inhibitor selection, genotyping has not yet been widely adopted in clinical practice. [ABSTRACT FROM AUTHOR]

Background: The widespread clinical use of lacosamide (LCM) has revealed significant individual differences in clinical response, with various reported influencing factors. However, it remains unclear how genetic factors related to the disposition and clinical response of LCM, as well as drug–drug interactions (DDIs), exert their influence on pediatric patients with epilepsy. Objectives: To evaluate the impact of genetic variations and DDIs on plasma LCM concentrations and clinical response. Design: Patients with epilepsy treated with LCM from June 2021 to March 2023 in the Children's Hospital of Nanjing Medical University were included in the analysis. Methods: The demographic information and laboratory examination data were obtained from the hospital information system. For the pharmacogenetic study, the left-over blood specimens, collected for routine plasma LCM concentration monitoring, were used to perform genotyping analysis for the selected 26 single nucleotide polymorphisms from 14 genes. The trough concentration/daily dose (C 0/D) ratio and efficacy outcomes were compared. Results: Patients achieved 90.1% and 68.9% responder rates in LCM mono- and add-on therapy, respectively. The genetic variant in the CYP2C19 *2 (rs4244285) was associated with a better responsive treatment outcome (odds ratio: 1.82; 95% confidence interval: 1.05–3.15; p = 0.031). In monotherapy, 36% of patients were CYP2C19 normal metabolizers (NMs), 49% were intermediate metabolizers (IMs), and 15% were poor metabolizers (PMs) carrying CYP2C19 *2 or *3. Of note, the C 0/D ratios of IMs and PMs were 9.1% and 39.6% higher than those of NMs, respectively. Similar results were in the add-on therapy group, and we also observed a substantial decrease in the C 0/D ratio when patients were concomitant with sodium channel blockers (SCBs). Conclusion: This study was the first to confirm that CYP2C19 *2 or *3 variants impact the disposition and treatment response of LCM in children with epilepsy. Moreover, concomitant with SCBs, particularly oxcarbazepine, also decreased plasma LCM concentration. Plain language summary: CYP2C19 genotype and sodium channel blockers in lacosamide-treated children with epilepsy: two major determinants of plasma lacosamide concentration or treatment efficacy This study examined the impact of genetic factors and drug combinations on the effectiveness and plasma concentrations of lacosamide, an antiseizure medication, in patients under 18. Analyzing blood samples from 316 patients at the Children's Hospital of Nanjing Medical University, researchers discovered that genetic variations in the CYP2C19 (i.e. *2 and *3), along with metabolic capacity, and co-medication with sodium channel blockers, all influence plasma lacosamide concentration. Understanding these genetic influences could inform personalized dosing strategies, improving the medication's management for pediatric epilepsy patients. [ABSTRACT FROM AUTHOR]

Wenhao Chen,1 Yuanliang Liu,2 Xunwei Deng,3 Bin Li,1 Hao Wang,1 Guoliang Wei,1 Kehui Chen,1 Shen Wang1 1Center for Cardiovascular Diseases, Meizhou People’s Hospital, Meizhou, People’s Republic of China; 2Department of Computer Tomography, Meizhou People’s Hospital, Meizhou, People’s Republic of China; 3Research Experimental Center, Meizhou People’s Hospital, Meizhou, People’s Republic of ChinaCorrespondence: Wenhao Chen, Center for Cardiovascular Diseases, Meizhou People’s Hospital, Meizhou, People’s Republic of China, Email 18319255493@163.comObjective: Cytochrome P450 2C19 (CYP2C19) is a major enzyme involved in the biotransformation and metabolism of various substances. Loss-of-function of the CYP2C19 gene represents downregulation of CYP2C19 enzyme indication limited or no enzymatic function, which may be, in turn, associated with some disease susceptibility. The relationship between CYP2C19 polymorphisms and susceptibility to premature coronary artery disease (PCAD) is not fully understood. This study aimed to assess this relationship.Methods: This study included 635 PCAD patients, and 548 age-matched non-CAD individuals as controls, from November 2019 to August 2023. The CYP2C19 rs4244285 (681G > A, &ast;2) and rs4986893 (636G > A, &ast;3) were genotyped, and the distribution of CYP2C19 polymorphisms between patients and controls and the relationship between CYP2C19 polymorphisms and PCAD risk were analyzed.Results: A total of 442 (37.4%), 543 (45.9%), and 198 (16.7%) individuals had CYP2C19 extensive metabolizer (EM) (&ast;1/&ast;1), intermediate metabolizer (IM) (&ast;1/&ast;2 and &ast;1/&ast;3), and poor metabolizer (PM) (&ast;2/&ast;2, &ast;2/&ast;3, and &ast;3/&ast;3) phenotypes, respectively. CYP2C19 &ast;2/&ast;2 genotype frequency was higher, &ast;1/&ast;1 genotype was lower in PCAD patients than controls. Individuals with CYP2C19 PM phenotype had higher triglyceride (TG) levels than those with CYP2C19 EM or IM phenotypes. Logistic regression analysis showed that body mass index (BMI) ≥ 24.0 kg/m2 (≥ 24.0 kg/m2 vs 18.5– 23.9 kg/m2, odds ratio (OR): 1.326, 95% confidence interval (CI): 1.041– 1.688, p = 0.022), smoking (OR: 1.974, 95% CI: 1.283– 3.306, p = 0.002), hypertension (OR: 1.327, 95% CI: 1.044– 1.687, p = 0.021), diabetes mellitus (OR: 1.390, 95% CI: 1.054– 1.834, p = 0.020), CYP2C19 PM phenotype (PM phenotype vs EM phenotype, OR: 1.701, 95% CI: 1.200– 2.411, p = 0.003), and CYP2C19 IM+PM phenotypes (IM+PM vs EM phenotype, OR: 1.369, 95% CI: 1.077– 1.740, p = 0.010) were associated with PCAD.Conclusion: CYP2C19 PM or IM+PM phenotypes, overweight, smoking, hypertension, and diabetes mellitus were associated with PCAD.Keywords: premature coronary artery disease, cytochrome P450, CYP2C19, loss-of-function

Abstract Objective Cytochrome P450 2C19 (CYP2C19) plays an vital role in the course of cardiovascular and cerebrovascular diseases by affecting lipid metabolism. Triglyceride-glucose (TyG) is a comprehensive index composed of triglyceride and blood glucose, has relationship with some diseases. There was no research report on the association CYP2C19 polymorphisms, TyG with premature cerebral infarction (CI) (onset ≤ 65 years old) susceptibility. Methods This study retrospectively analyzed 1953 CI patients aged ≤ 65 years old from December 2018 to March 2024, and 1919 age-matched individuals with non-CI as controls. The relationship between CYP2C19 polymorphisms, TyG and premature CI risk were analyzed. Results The proportion of hypertension, and diabetes mellitus in patients with premature CI was higher than those in controls. The serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein-cholesterol (LDL-C), and TyG levels in patients with premature CI were significantly higher than those in controls (all p

Wendao Han, Nating Xiong, Renkai Zhong, Zhongyi Pan Department of Blood Transfusion, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of ChinaCorrespondence: Wendao Han, Department of Blood Transfusion, Meizhou People’s Hospital, Meizhou, People’s Republic of China, Email 443567914@qq.comObjective: Atherosclerosis (AS) is a sustained chronic vascular inflammatory response caused by lipid metabolism disorders and immune response disorders and is the main cause of premature (men ≤ 55 years old, women ≤ 65 years old) myocardial infarction (PMI). Cytochrome P450 2C19 (CYP2C19) (related to vascular function and lipid metabolism) and peripheral immune cell levels and plays an important role in the course of AS. The association CYP2C19 polymorphisms, comprehensive immunoinflammatory indices with PMI susceptibility is unclear.Methods: This study included 485 PMI patients, and 639 age-matched non-PMI individuals as controls, from January 2019 to March 2024. The relationship between CYP2C19 polymorphisms, peripheral immunoinflammatory indices (pan-immune inflammation value (PIV), systemic immune inflammation index (SII), and system inflammation response index (SIRI)) and PMI risk were analyzed.Results: The inflammatory indices levels in PMI patients were higher than those in controls (all p< 0.05). The frequencies of the CYP2C19 &ast;1/&ast;2 and &ast;2/&ast;2 genotypes were higher, while the frequency of the &ast;1/&ast;1 genotype was lower in the PMI patients than those in controls. The cut-off values of TC, TG, LDL-C, PIV, SII, and SIRI were 5.065, 1.305, 2.805, 410.485, 869.645, and 1.495 for distinguishing PMI, respectively. Logistic regression analysis showed that male (odds ratio (OR): 1.607, 95% confidence interval (CI): 1.134– 2.277, p=0.008), history of smoking (OR: 7.108, 95% CI: 4.351– 11.614, p< 0.001), diabetes mellitus (OR: 4.906, 95% CI: 3.333– 7.223, p< 0.001), CYP2C19 poor metabolizer (PM) (&ast;2/&ast;2, &ast;2/&ast;3, and &ast;3/&ast;3) (OR: 2.147, 95% CI: 1.279– 3.603, p=0.004), and high TG (≥ 1.305 vs < 1.305, OR: 2.598, 95% CI: 1.864– 3.623, p< 0.001) and SIRI level (≥ 1.495 vs < 1.495, OR: 2.495, 95% CI: 1.432– 4.349, p=0.001) were independent risk factors for PMI.Conclusion: CYP2C19 PM phenotype, high SIRI level (≥ 1.495) and TG level (≥ 1.305), male, history of smoking, and diabetes mellitus were independently associated with PMI susceptibility.Keywords: premature myocardial infarction, system inflammation response index, CYP2C19, polymorphism

Voriconazole pharmacokinetics (PK) are known to be affected by genetic polymorphisms of drug-metabolizing enzymes such as CYP2C19 ; however, such information is limited for the pediatric population. The primary aim of this study is to establish a voriconazole PK model incorporating CYP2C19 phenotypes in Japanese children with malignancy or inborn errors of immunity. CYP2C19 genotypes were assessed by whole-genome genotyping and defined as follows: *17/*17: ultrarapid metabolizer (URM), *1/*17: rapid metabolizer (RM), *1/*1:normal metabolizer (NM), *1/*2, *1/*3, *2/*17:intermediate metabolizer (IM), and *2/*2, *2/*3, *3/*3: poor metabolizer (PM). Population PK analysis was performed. The voriconazole serum concentration profile was described by a two-compartment model with first-order absorption, mixed linear and nonlinear (Michaelis-Menten) elimination. Voriconazole concentration data were available from 60 patients with a median age of 5.3 years. The phenotypes predicted from CYP2C19 genotypes were RM in 1 (2 %), NM in 21 (35 %) patients, IM in 27 (45 %) patients, and PM in 11 (18 %) patients. Underlying diseases included 38 (63%) patients with hematological malignancy and 18 (30 %) patients with inborn errors of immunity. Among the CYP2C19 phenotypes, PM was predicted to show complete inhibition (the degree of V max inhibition [V max, inh ] = 100 %; V max = 0). The estimated parameters of V max,inh were +0.8 higher in patients with gamma-glutamyl transpeptidase (γ-GTP) Grade 2 or higher and +2.7 higher when C -reactive protein (CRP) levels were 2.0 mg/dL or higher. CYP2C19 genetic polymorphisms, γ-GTP, and CRP affect V max,inh of voriconazole in children with malignancy or inborn errors of immunity. [ABSTRACT FROM AUTHOR]

Abstract Background Helicobacter pylori eradication therapy based on antimicrobial susceptibility in Vietnamese children currently get low efficiency. There are causes of treatment failure, among host genetic factors namely MDR1 C3435T and CYP2C19 affect the absorption and metabolism of proton pump inhibitors - a crucial component of eradication therapy. The study aimed to investigate the effect of MDR1 C3435T and CYP2C19 genetic polymorphisms on the cure rate. Methods 207 pediatric patients with gastritis and peptic ulcer infecting Helicobacter pylori completed the eradication therapy based on antimicrobial susceptibility with proton pump inhibitor esomeprazole. Eradication efficacy was assessed after at least 4 weeks by the urease breath test. MDR1 C3435T genetic polymorphism and CYP2C19 genotype were determined using a sequencing method based on Sanger’s principle. Results Among 207 children recruited in this study, the ratio of CYP2C19 EM, IM, and PM phenotypes was 40.1%, 46.4%, and 16.9%, respectively. The patient with MDR1 3435 C/C polymorphism accounted for 43.0%, MDR1 3435 C/T was 40.1%, and MDR1 3435T/T was 16.9%. The cure rate of Helicobacter pylori infection in patients with CYP2C19 EM genotype was 78.3%; 83.3% of those with the IM genotype, and PM genotype was 96,4% (p = 0.07). Successful eradication rates for Helicobacter pylori were 85.4%, 86.7%, and 68.6% in patients with the MDR1 3435 C/C, C/T, and T/T, respectively (p = 0.02). Multiple logistic regression analysis found that MDR1 C3435T genetic polymorphisms of patients were significant independent risk factors for treatment failure, and CYP2C19 genotype did not affect Helicobacter pylori eradication. Conclusions The Helicobacter pylori eradication rates by regimens based on antibiotic susceptibility and esomeprazole were not significantly different between the CYP2C19 phenotypes. The MDR1 C3435T polymorphism is one of the factors impacting Helicobacter pylori eradication results in children.

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]

Voriconazole is the first‐line treatment for invasive aspergillosis. Its pharmacokinetics exhibit considerable inter‐ and intra‐individual variability. The purpose of this study was to investigate the effects of CYP2C19, CYP2C9, CYP3A4, and FMO3 genetic polymorphisms and sex on the pharmacokinetics of voriconazole in healthy Chinese adults receiving single‐dose and multiple‐dose voriconazole, to provide a reference for its clinical individualized treatment. A total of 123 healthy adults were enrolled in the study, with 108 individuals and 15 individuals in the single‐dose and multiple‐dose doses, respectively. Plasma voriconazole concentrations were measured using a validated LC‐MS/MS method, and pharmacokinetics parameters were calculated using the non‐compartmental method with WinNonlin 8.2. CYP2C19, CYP2C9, CYP3A4, and FMO3 single‐nucleotide polymorphisms were sequenced using the Illumina Hiseq X‐Ten platform. The results suggested that CYP2C19 genetic polymorphisms significantly affected the pharmacokinetics of voriconazole at single doses of 4, 6, and 8 mg/kg and multiple doses of voriconazole. CYP3A4 rs2242480 had a significant effect on AUC0‐∞ (area under the plasma concentration‐time curve from time 0 to infinity) and MRT (mean residence time) of voriconazole at a single dose of 4 mg/kg in CYP2C19 extensive metabolizer. Regardless of the CYP2C19 genotype, CYP2C9 rs1057910 and FMO3 rs2266780 were not associated with the pharmacokinetics of voriconazole at three single‐dose levels or multiple doses. No significant differences in most voriconazole pharmacokinetics parameters were noted between male and female participants after single and multiple dosing. For patients receiving voriconazole treatment, CYP2C19 genetic polymorphisms should be genotyped for its precision administration. In contrast, based on our study of healthy Chinese adults, it seems unnecessary to consider the effects of CYP2C9, CYP3A4, and FMO3 genetic polymorphisms on voriconazole pharmacokinetics. [ABSTRACT FROM AUTHOR]

This article presents a study on the distribution of cytochrome P450 (CYP450) alleles in the Danish population. CYP450 enzymes are important for drug metabolism, and genetic variations in the genes encoding these enzymes can impact drug response. The study compared genotype data from different genotyping platforms and found that the CYP2C19*17 and CYP2C9*2 alleles were more common than the CYP2C19*2 and CYP2C9*3 alleles. The results provide valuable insights into the genetic variability of these enzymes in the Danish population and suggest that the Illumina GSA platform could be useful for identifying drug-gene interactions. [Extracted from the article]

Background: Helicobacter pylori eradication therapy based on antimicrobial susceptibility in Vietnamese children currently get low efficiency. There are causes of treatment failure, among host genetic factors namely MDR1 C3435T and CYP2C19 affect the absorption and metabolism of proton pump inhibitors - a crucial component of eradication therapy. The study aimed to investigate the effect of MDR1 C3435T and CYP2C19 genetic polymorphisms on the cure rate. Methods: 207 pediatric patients with gastritis and peptic ulcer infecting Helicobacter pylori completed the eradication therapy based on antimicrobial susceptibility with proton pump inhibitor esomeprazole. Eradication efficacy was assessed after at least 4 weeks by the urease breath test. MDR1 C3435T genetic polymorphism and CYP2C19 genotype were determined using a sequencing method based on Sanger's principle. Results: Among 207 children recruited in this study, the ratio of CYP2C19 EM, IM, and PM phenotypes was 40.1%, 46.4%, and 16.9%, respectively. The patient with MDR1 3435 C/C polymorphism accounted for 43.0%, MDR1 3435 C/T was 40.1%, and MDR1 3435T/T was 16.9%. The cure rate of Helicobacter pylori infection in patients with CYP2C19 EM genotype was 78.3%; 83.3% of those with the IM genotype, and PM genotype was 96,4% (p = 0.07). Successful eradication rates for Helicobacter pylori were 85.4%, 86.7%, and 68.6% in patients with the MDR1 3435 C/C, C/T, and T/T, respectively (p = 0.02). Multiple logistic regression analysis found that MDR1 C3435T genetic polymorphisms of patients were significant independent risk factors for treatment failure, and CYP2C19 genotype did not affect Helicobacter pylori eradication. Conclusions: The Helicobacter pylori eradication rates by regimens based on antibiotic susceptibility and esomeprazole were not significantly different between the CYP2C19 phenotypes. The MDR1 C3435T polymorphism is one of the factors impacting Helicobacter pylori eradication results in children. [ABSTRACT FROM AUTHOR]

Pharmaceutical researchers are continually searching for techniques to improve both drug development processes and patient outcomes. An area of recent interest is the potential for machine learning (ML) applications within pharmacology. One such application not yet given close study is the unsupervised clustering of plasma concentration-time curves, hereafter, pharmacokinetic (PK) curves. In this paper, we present our findings on how to cluster PK curves by their similarity. Specifically, we find clustering to be effective at identifying similar-shaped PK curves and informative for understanding patterns within each cluster of PK curves. Because PK curves are time series data objects, our approach utilizes the extensive body of research related to the clustering of time series data as a starting point. As such, we examine many dissimilarity measures between time series data objects to find those most suitable for PK curves. We identify Euclidean distance as generally most appropriate for clustering PK curves, and we further show that dynamic time warping, Fréchet, and structure-based measures of dissimilarity like correlation may produce unexpected results. As an illustration, we apply these methods in a case study with 250 PK curves used in a previous pharmacogenomic study. Our case study finds that an unsupervised ML clustering with Euclidean distance, without any subject genetic information, is able to independently validate the same conclusions as the reference pharmacogenomic results. To our knowledge, this is the first such demonstration. Further, the case study demonstrates how the clustering of PK curves may generate insights that could be difficult to perceive solely with population level summary statistics of PK metrics. [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]

Variability in hepatic cytochrome P450 (CYP) enzymes such as 2C19 and 2D6 may influence side-effect and efficacy outcomes for antipsychotics. Aripiprazole and risperidone are two commonly prescribed antipsychotics, metabolized primarily through CYP2D6. Here, we aimed to provide an overview of the effect of CYP2C19 and CYP2D6 on side-effects of aripiprazole and risperidone, and expand on existing literature by critically examining methodological issues associated with pharmacogenetic studies. A PRISMA compliant search of six electronic databases (Pubmed, PsychInfo, Embase, Central, Web of Science, and Google Scholar) identified pharmacogenetic studies on aripiprazole and risperidone. 2007 publications were first identified, of which 34 were included. Quality of literature was estimated using Newcastle-Ottowa Quality Assessment Scale (NOS) and revised Cochrane Risk of Bias tool. The average NOS score was 5.8 (range: 3–8) for risperidone literature and 5 for aripiprazole (range: 4–6). All RCTs on aripiprazole were rated as high risk of bias, and four out of six for risperidone literature. Study populations ranged from healthy volunteers to inpatient individuals in psychiatric units and included adult and pediatric samples. All n = 34 studies examined CYP2D6. Only one study genotyped for CYP2C19 and found a positive association with neurological side-effects of risperidone. Most studies did not report any relationship between CYP2D6 and any side-effect outcome. Heterogeneity between and within studies limited the ability to synthesize data and draw definitive conclusions. Studies lacked statistical power due to small sample size, selective genotyping methods, and study design. Large-scale randomized trials with multiple measurements, providing robust evidence on this topic, are suggested. • Personalizing psychiatric medication may be achieved through pharmacogenetics. • Metabolic enzymes CYP2C19 and CYP2D6 are of interest for psychopharmacology. • Combining all available data suggests that empirical evidence remains mixed. • Some evidence exists for a link between CYP2D6 and side-effects of risperidone. • Research on CYP2C19 and antipsychotic medication is lacking. [ABSTRACT FROM AUTHOR]

Purpose: Chronic kidney disease (CKD) is a risk factor for ischemic and bleeding events with dual antiplatelet therapy after percutaneous coronary intervention (PCI). Whether the presence of CYP2C19 loss of function (LOF) alleles modifies this risk, and whether a genotype-guided (GG) escalation of P2Y12 inhibitor therapy post PCI is safe in this population is unclear. Methods: This was a post hoc analysis of randomized patients in TAILOR PCI. Patients were divided into two groups based on estimated glomerular filtration rate (eGFR) threshold of < 60 ml/min/1.73 m2 for CKD (n = 539) and non-CKD (n = 4276). The aggregate of cardiovascular death, stroke, myocardial infarction, stent thrombosis, and severe recurrent coronary ischemia at 12-months post-PCI was assessed as the primary endpoint. Secondary endpoint was major or minor bleeding. Results: Mean (standard deviation) eGFR among patients with CKD was 49.5 (8.4) ml/min/1.72 m2. Among all patients, there was no significant interaction between randomized strategy and CKD status for any endpoint. Among LOF carriers, the interaction between randomized strategy and CKD status on composite ischemic outcome was not significant (p = 0.2). GG strategy was not associated with an increased risk of bleeding in either CKD group. Conclusions: In this exploratory analysis, escalation of P2Y12 inhibitor therapy following a GG strategy did not reduce the primary outcome in CKD. However, P2Y12 inhibitor escalation following a GG strategy was not associated with increased bleeding risk in CKD. Larger studies in CKD are needed. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT01742117?term=TAILOR-PCI&draw=2&rank=1. NCT01742117. [ABSTRACT FROM AUTHOR]

IntroductionPharmacogenetics (PGx) holds promise for optimizing psychotropic medication use, with CYP2D6 and CYP2C19 identified as key genes in antidepressant treatment. However, few studies have explored the genetic variants of these genes in real-world settings for patients experiencing ineffectiveness or adverse drug reactions (ADRs) to antidepressants.MethodsThis case series includes 40 patients who underwent PGx testing due to antidepressant ineffectiveness or ADRs between June 2020 and April 2022. We describe the patients' demographic, clinical, and genetic characteristics and assess the value of PGx testing based on feedback from their psychiatrists.ResultsThe most common diagnoses were major depressive disorder (60.0%) and post-traumatic stress disorder (30.0%). Ineffectiveness was reported in 65.0% of patients, ADRs in 2.5%, and both in 32.5%. The antidepressants involved included SSRIs (45.0%), SNRIs (27.5%), atypical antidepressants (20.0%), and tricyclics (17.5%). Only 17.5% of patients had normal CYP2D6 and CYP2C19 metabolic activity. Actionable genetic variants were identified in 22.0% of CYP2D6/CYP2C19-antidepressant-response pairs. PGx recommendations were followed in 92.7% of cases, with significant improvement in ADRs reported in 71.4% of patients and efficacy improvement in 79.5%.DiscussionOur findings suggest that PGx testing can guide prescribing decisions for patients with antidepressant ineffectiveness or ADRs. The relatively high prevalence of genetic variants affecting pharmacokinetics supports the broader adoption of PGx testing in psychiatric practice.

Aim: The genetic polymorphism of CYP2C19 influences clopidogrel metabolism and resistance. Aim was to assess the association between CYP2C19 loss of function variation, clopidogrel resistance based on platelet reactivity units and clinical outcomes. Methods: A total of 668 patients of Acute Coronary Sundrome (ACS) who underwent Percutaneous Coronary Intervention (PCI) were subjected to genetic screening and 143 patients undrewent platelet function test to study the association between drug metabolization and its effects based on platelet reactivity unit values. Results: Clopidogrel resistance with CYP2C 19 loss of function variation was noted in 54.64% of patients. Clinical outcomes, such as target vessel revascularization, target lesion revascularization, in-stent restenosis, and stent thrombosis, were also studied. Conclusion: CYP2C19 loss of function variation is strongly associated with clopidogrel resistance and adverse clinical outcomes.

Abstract Background Tailoring antidepressant drugs (AD) to patients’ genetic drug-metabolism profile is promising. However, literature regarding associations of ADs’ treatment effect and/or side effects with drug metabolizing genes CYP2D6 and CYP2C19 has yielded inconsistent results. Therefore, our aim was to longitudinally investigate associations between CYP2D6 (poor, intermediate, and normal) and CYP2C19 (poor, intermediate, normal, and ultrarapid) metabolizer-status, and switching/discontinuing of ADs. Next, we investigated whether the number of perceived side effects differed between metabolizer statuses. Methods Data came from the multi-site naturalistic longitudinal cohort Netherlands Study of Depression and Anxiety (NESDA). We selected depression- and/or anxiety patients, who used AD at some point in the course of the 9 years follow-up period (n = 928). Medication use was followed to assess patterns of AD switching/discontinuation over time. CYP2D6 and CYP2C19 alleles were derived using genome-wide data of the NESDA samples and haplotype data from the PharmGKB database. Logistic regression analyses were conducted to investigate the association of metabolizer status with switching/discontinuing ADs. Mann–Whitney U-tests were conducted to compare the number of patient-perceived side effects between metabolizer statuses. Results No significant associations were observed of CYP metabolizer status with switching/discontinuing ADs, nor with the number of perceived side effects. Conclusions We found no evidence for associations between CYP metabolizer statuses and switching/discontinuing AD, nor with side effects of ADs, suggesting that metabolizer status only plays a limited role in switching/discontinuing ADs. Additional studies with larger numbers of PM and UM patients are needed to further determine the potential added value of pharmacogenetics to guide pharmacotherapy.

Abstract Metabolism of praziquantel (PZQ), a racemic mixture and the only drug approved to treat S. mansoni infection, is mediated by genetically polymorphic enzymes. Periodic school-based mass drug administration (MDA) with PZQ is the core intervention to control schistosomiasis. However data on the impact of pharmacogenetic variation, nutrition, and infection status on plasma PZQ exposure is scarce. We investigated genetic and non-genetic factors influencing PZQ plasma concentration and its metabolic ratios (trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ). Four hundred forty-six school children aged 7–15 years from four primary schools in southern Ethiopia who received albendazole and PZQ preventive chemotherapy through MDA campaign were enrolled. Genotyping for common functional variants of CYP3A4 (*1B), CYP3A5 (*3, *6), CYP2C19 (*2, *3, *17), CYP2C9 (*2, *3), and CYP2J2*7 was performed. Plasma concentrations of PZQ, trans-4-OH-PZQ, and cis-4-OH-PZQ were quantified using UPLCMS/MS. Carriers of CYP2C19 defective variant alleles (*2 and *3) had significantly higher mean PZQ plasma concentration than CYP2C19*1/*1 or *17 carriers (p = 0.005). CYP2C19*1/*1 and CYP2C19*17 carriers had higher trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ metabolic ratios compared with CYP2C19*2 or *3 carriers (p

Abstract Purpose We aimed to investigated the influencing risk factors of voriconazole-induced liver injury in Uygur pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Methods This was a prospective cohort design study. High-performance liquid chromatography-mass spectrometry was employed to monitor voriconazole concentration. First-generation sequencing was performed to detect gene polymorphisms. Indicators of liver function were detected at least once before and after voriconazole therapy. Results Forty-one patients were included in this study, among which, 15 patients (36.6%) had voriconazole-induced liver injury. The proportion of voriconazole trough concentration > 5.5 μg·mL−1 patients within the DILI group (40.0%) was significantly higher compared to the control group (15.4%) (p 0.05). Conclusion There was a significant correlation between voriconazole-induced liver injury and voriconazole trough concentration in high-risk Uygur pediatric patients with allogeneic HSCT.

Abstract Objective To study the distribution characteristics of CYP2C19 polymorphisms in patients suffering from stroke in Han Chinese patients. Method PCR and DNA microarray chip technology were used to detect the CYP2C19 genotype of 549 patients with stroke, and the genotype, allele frequency and metabolic type of patients with different sexes, ages and types of infarctions and the independent risk factors for clopidogrel resistance were analyzed. Results Six genotypes were detected in these 549 patients. A total of 233 (42.44%) patients had the heterozygous allele *1/*2, which was the most prevalent, followed by the homozygous wild-type allele *1/*1 (191, 34.79%). A total of 30 (5.46%) patients possessed the heterozygous allele *1/*3, and 65 (11.84%) patients had the homozygous mutant allele *2/*2. Twenty-nine (5.28%) patients had the compound heterozygous mutant allele *2/*3, and only 1 patient had the homozygous mutant allele *3/*3. The distribution of genotypes, alleles, and metabolic types did not change significantly (P > 0.05) by sex, age, or type of stroke. In addition, no independent risk factors for clopidogrel resistance were found in this analysis. Conclusion The distribution of CYP2C19 genotypes, allele frequencies, and metabolic types in patients with stroke in Han Chinese patients were not correlated with sex, age, or infarction type. The possibilities of hyperglycemia, hypercholesterolemia, hypertriglyceridemia, hypo-HDL-cholesterolemia, hyper-LDL-cholesterolemia and high blood pressure were not statistically associated with CYP2C19 genotypes. CYP2C19 gene polymorphism detection is recommended for patients who are available, and during treatment, the CYP2C19 genotype can be used to guide personalized precise medication use in patients with stroke.

Clopidogrel, is a standard treatment in the prevention of major adverse cardiovascular events (MACE) in patients with coronary artery disease (CAD). Clopidogrel response is highly variable, mainly due to the presence of polymorphisms in the genes involved in drug metabolism. The aim of this study was to evaluate the association between the presence of the ABCB1 C3435T and CYP2C19*2 polymorphism and the clinical outcome in patients with CAD treated with clopidogrel. A total of 96 patients with CAD were included in the study. Genomic DNA from peripheral blood was extracted from all patients with standard phenol/chloroform protocol. The genotyping was performed by Real-Time PCR using TagMan assays. The frequency of the reduced-function allele, in both genes, was higher in patients with negative outcome (36.36% vs 21.15%). A negative clinical outcome and an increased risk for MACE was observed in patients with concomitant inheritance of the CYP2C19 *1/*2 and ABCB1 CT genotype vs patients with other genotypes (22.73% vs 9.62%; OR 3.455; 95% CI= [0.936–12.743], p=0.05722. A trend towards higher risk of MACE was also noted in carriers of the CYP2C19*1/*1 and ABCB1 CC/CT genotype. Our results support the data on the association of the CYP2C19 *2 alone, or in combination with the ABCB1 C polymorphism with the increased risk of MACE. The results also indicate that the presence of ABCB1 C343T polymorphism might be potentially considered as independent predictor of MACE in patients on clopidogrel. However, these results are preliminary and should be confirmed on a larger number of patients.

Background: Tailoring antidepressant drugs (AD) to patients’ genetic drug-metabolism profile is promising. However, literature regarding associations of ADs’ treatment effect and/or side effects with drug metabolizing genes CYP2D6 and CYP2C19 has yielded inconsistent results. Therefore, our aim was to longitudinally investigate associations between CYP2D6 (poor, intermediate, and normal) and CYP2C19 (poor, intermediate, normal, and ultrarapid) metabolizer-status, and switching/discontinuing of ADs. Next, we investigated whether the number of perceived side effects differed between metabolizer statuses. Methods: Data came from the multi-site naturalistic longitudinal cohort Netherlands Study of Depression and Anxiety (NESDA). We selected depression- and/or anxiety patients, who used AD at some point in the course of the 9 years follow-up period (n = 928). Medication use was followed to assess patterns of AD switching/discontinuation over time. CYP2D6 and CYP2C19 alleles were derived using genome-wide data of the NESDA samples and haplotype data from the PharmGKB database. Logistic regression analyses were conducted to investigate the association of metabolizer status with switching/discontinuing ADs. Mann–Whitney U-tests were conducted to compare the number of patient-perceived side effects between metabolizer statuses. Results: No significant associations were observed of CYP metabolizer status with switching/discontinuing ADs, nor with the number of perceived side effects. Conclusions: We found no evidence for associations between CYP metabolizer statuses and switching/discontinuing AD, nor with side effects of ADs, suggesting that metabolizer status only plays a limited role in switching/discontinuing ADs. Additional studies with larger numbers of PM and UM patients are needed to further determine the potential added value of pharmacogenetics to guide pharmacotherapy. [ABSTRACT FROM AUTHOR]

The effectiveness of lipid-lowering therapies may be insufficient in high-risk cardiovascular patients and depends on the genetic variability of drug-metabolizing enzymes. Customizing statin therapy, including treatment with atorvastatin, may improve clinical outcomes. Currently, there is a lack of guidelines allowing the prediction of the therapeutic efficacy of lipid-lowering statin therapy. This study aimed to determine the effects of clinically significant gene variants of CYP2C19 on atorvastatin therapy in patients with acute coronary syndromes. In total, 92 patients with a confirmed diagnosis of ST-elevation myocardial infarction (STEMI) or non-ST-elevation myocardial infarction (NSTEMI) were sequenced for target regions within the CYP2C19 gene on the Illumina Miniseq system. The CYP2C19 poor metabolizer phenotype (carriers of CYP2C19*2, CYP2C19*4, and CYP2C19*8 alleles) was detected in 29% of patients. These patients had significantly lower responses to treatment with atorvastatin than patients with the normal metabolizer phenotype. CYP2C19-metabolizing phenotype, patient age, and smoking increased the odds of undertreatment in patients (∆LDL-C (mmol/L) < 1). These results revealed that the CYP2C19 phenotype may significantly impact atorvastatin therapy personalization in patients requiring LDL lipid-lowering therapy. [ABSTRACT FROM AUTHOR]

Pharmacogenomics is the examination of how genetic variation influences drug metabolism and response, in terms of both efficacy and safety. In cardiovascular disease, patient‐specific diplotypes determine phenotypes, thereby influencing the efficacy and safety of drug treatments, including statins, antiarrhythmics, anticoagulants and antiplatelets. Notably, polymorphisms in key genes, such as CYP2C9, CYP2C19, VKORC1 and SLCO1B1, significantly impact the outcomes of treatment with clopidogrel, warfarin and simvastatin. Furthermore, the CYP2C19 polymorphism influences the pharmacokinetics and safety of the novel hypertrophic cardiomyopathy inhibitor, mavacamten. In this review, we critically assess the clinical application of pharmacogenomics in cardiovascular disease and delineate present and future utilization of pharmacogenomics. This includes insights into identifying missing heritability, the integration of whole genome sequencing and the application of polygenic risk scores to enhance the precision of personalized drug therapy. Our discussion encompasses health economic analyses that underscore the cost benefits associated with pre‐emptive genotyping for warfarin and clopidogrel treatments, albeit acknowledging the need for further research in this area. In summary, we contend that cardiovascular pharmacogenomic analyses are underpinned by a wealth of evidence, and implementation is already occurring for some of these gene–drug pairs, but as with any area of medicine, we need to continually gather more information to optimize the use of pharmacogenomics in clinical practice. [ABSTRACT FROM AUTHOR]

This document summarizes a pilot study conducted in Denmark to assess the agreement between publicly funded genotyping tests and phenotype classification for certain genes. The study found inconsistencies in genotype and phenotype agreement between three laboratories, highlighting the need for standardization in pharmacogenetic testing. The document also discusses the lack of national alignment between laboratories in Denmark, which poses challenges in the use and implementation of pharmacogenetic testing. The study recommends continuous updating of the phenotype approach and alignment of genotyping and phenotyping classifications to ensure consistent implementation of pharmacogenetic testing in Denmark. The document also references various guidelines and studies related to pharmacogenetic testing in mental health care settings. [Extracted from the article]

Objective: To study the distribution characteristics of CYP2C19 polymorphisms in patients suffering from stroke in Han Chinese patients. Method: PCR and DNA microarray chip technology were used to detect the CYP2C19 genotype of 549 patients with stroke, and the genotype, allele frequency and metabolic type of patients with different sexes, ages and types of infarctions and the independent risk factors for clopidogrel resistance were analyzed. Results: Six genotypes were detected in these 549 patients. A total of 233 (42.44%) patients had the heterozygous allele *1/*2, which was the most prevalent, followed by the homozygous wild-type allele *1/*1 (191, 34.79%). A total of 30 (5.46%) patients possessed the heterozygous allele *1/*3, and 65 (11.84%) patients had the homozygous mutant allele *2/*2. Twenty-nine (5.28%) patients had the compound heterozygous mutant allele *2/*3, and only 1 patient had the homozygous mutant allele *3/*3. The distribution of genotypes, alleles, and metabolic types did not change significantly (P > 0.05) by sex, age, or type of stroke. In addition, no independent risk factors for clopidogrel resistance were found in this analysis. Conclusion: The distribution of CYP2C19 genotypes, allele frequencies, and metabolic types in patients with stroke in Han Chinese patients were not correlated with sex, age, or infarction type. The possibilities of hyperglycemia, hypercholesterolemia, hypertriglyceridemia, hypo-HDL-cholesterolemia, hyper-LDL-cholesterolemia and high blood pressure were not statistically associated with CYP2C19 genotypes. CYP2C19 gene polymorphism detection is recommended for patients who are available, and during treatment, the CYP2C19 genotype can be used to guide personalized precise medication use in patients with stroke. [ABSTRACT FROM AUTHOR]

An ABCD-GENE (age, body mass index, chronic kidney disease, diabetes, and CYP2C19 genetic variants) score ≥10 predicts reduced clopidogrel effectiveness, but its association with response to alternative therapy remains unclear. The aim of this study was to evaluate the association between ABCD-GENE score and the effectiveness of clopidogrel vs alternative P2Y 12 inhibitor (prasugrel or ticagrelor) therapy after percutaneous coronary intervention (PCI). A total of 4,335 patients who underwent PCI, CYP2C19 genotyping, and P2Y 12 inhibitor treatment were included. The primary outcome was major atherothrombotic events (MAE) within 1 year after PCI. Cox regression was performed to assess event risk in clopidogrel-treated (reference) vs alternatively treated patients, with stabilized inverse probability weights derived from exposure propensity scores after stratifying by ABCD-GENE score and further by CYP2C19 loss-of-function (LOF) genotype. Among patients with scores <10 (n = 3,200), MAE was not different with alternative therapy vs clopidogrel (weighted HR: 0.89; 95% CI: 0.65-1.22; P = 0.475). The risk for MAE also did not significantly differ by treatment among patients with scores ≥10 (n = 1,135; weighted HR: 0.75; 95% CI: 0.51-1.11; P = 0.155). Among CYP2C19 LOF allele carriers, MAE risk appeared lower with alternative therapy in both the group with scores <10 (weighted HR: 0.50; 95% CI: 0.25-1.01; P = 0.052) and the group with scores ≥10 (weighted HR: 0.48; 95% CI: 0.29-0.80; P = 0.004), while there was no difference in the group with scores <10 and no LOF alleles (weighted HR: 1.03; 95% CI: 0.70-1.51; P = 0.885). These data support the use of alternative therapy over clopidogrel in CYP2C19 LOF allele carriers after PCI, regardless of ABCD-GENE score, while clopidogrel is as effective as alternative therapy in non-LOF patients with scores <10. [Display omitted] [ABSTRACT FROM AUTHOR]

Peripheral arterial disease (PAD) affects approximately 236 million people worldwide. Therefore, this study aimed to investigate the relationship between CYP2C19 genotype polymorphisms and clopidogrel resistance (CR) following revascularization in patients with PAD. In total, 345 patients who underwent PAD revascularization were monitored for five years and risk factors for ischemic events were identified. Platelet reactivity and CYP2C19 genotypes were measured, and patients were classified as normal, intermediate, or poor metabolizers based on their genotypes. The study endpoint was defined as an ischemic event, that encompassed major adverse cardiovascular or limb events, or all-cause death. In this study, ischemic events following PAD revascularization were associated with patient age, prior minor amputation, the Rutherford category before revascularization, indications for revascularization, index ankle-branchial index before revascularization, CYP2C19 phenotypes, and CR. Intermediate and poor metabolism, the Rutherford category before revascularization, and CR were independent risk factors for ischemic events in patients after PAD revascularization. Similarly, intermediate and poor metabolism, the Rutherford category before revascularization, and CR were independent risk factors for ischemic events in patients with PAD after revascularization within five years. Intermediate and poor metabolizers had a higher platelet reactivity and risk of CR than normal metabolizers. However, poor metabolizers had a higher platelet reactivity and risk of CR than intermediate metabolizers. Furthermore, the hazard ratio for ischemic events increased with platelet reactivity. This effect was more prevalent in intermediate and poor metabolizers than in normal metabolizers. Ischemic events in patients after PAD revascularization were affected by independent risk factors. Decreased clopidogrel metabolism increased the platelet reactivity and CR in patients after PAD revascularization. Furthermore, high platelet reactivity was associated with an increased risk of ischemic events in patients with intermediate and poor metabolism. [Display omitted] • CYP2C19 phenotype and CR effects after revascularization for PAD remain unclear. • We evaluated these effects on ischemic events after revascularization over 5 years. • CYP2C19 phenotype and CR were independent risk factors for ischemic events. • Patients with impaired clopidogrel metabolism had a higher risk of CR. [ABSTRACT FROM AUTHOR]

Background: Venlafaxine (VEN) is a commonly utilized medication for alleviating depression and anxiety disorders. The presence of genetic polymorphisms gives rise to considerable variations in plasma concentrations across different phenotypes. This divergence in phenotypic responses leads to notable differences in both the efficacy and tolerance of the drug. Purpose: A physiologically based pharmacokinetic (PBPK) model for VEN and its metabolite O-desmethylvenlafaxine (ODV) to predict the impact of CYP2D6 and CYP2C19 gene polymorphisms on VEN pharmacokinetics (PK). Methods: The parent-metabolite PBPK models for VEN and ODV were developed using PK-Sim® and MoBi®. Leveraging prior research, derived and implemented CYP2D6 and CYP2C19 activity score (AS)-dependent metabolism to simulate exposure in the drug-gene interactions (DGIs) scenarios. The model's performance was evaluated by comparing predicted and observed values of plasma concentration–time (PCT) curves and PK parameters values. Results: In the base models, 91.1%, 94.8%, and 94.6% of the predicted plasma concentrations for VEN, ODV, and VEN + ODV, respectively, fell within a twofold error range of the corresponding observed concentrations. For DGI scenarios, these values were 81.4% and 85% for VEN and ODV, respectively. Comparing CYP2D6 AS = 2 (normal metabolizers, NM) populations to AS = 0 (poor metabolizers, PM), 0.25, 0.5, 0.75, 1.0 (intermediate metabolizers, IM), 1.25, 1.5 (NM), and 3.0 (ultrarapid metabolizers, UM) populations in CYP2C19 AS = 2.0 group, the predicted DGI AUC0-96 h ratios for VEN were 3.65, 3.09, 2.60, 2.18, 1.84, 1.56, 1.34, 0.61, and for ODV, they were 0.17, 0.35, 0.51, 0.64, 0.75, 0.83, 0.90, 1.11, and the results were similar in other CYP2C19 groups. It should be noted that PK differences in CYP2C19 phenotypes were not similar across different CYP2D6 groups. Conclusions: In clinical practice, the impact of genotyping on the in vivo disposition process of VEN should be considered to ensure the safety and efficacy of treatment. [ABSTRACT FROM AUTHOR]

Previous results demonstrated that CYP2D6 and CYP2C19 gene variants affect serum concentrations of antidepressants. We implemented a PGx service determining gene variants in CYP2D6 and CYP2C19 in our clinical routine care and report on our first patient cohort. We analysed CYP2D6 and CYP2C19 allele, genotype, and phenotype frequencies, and actionable pharmacogenetic variants in this German psychiatric inpatient cohort. Two-tailed z-test was used to investigate for differences in CYP2D6 and CYP2C19 phenotypes and actionable/non-actionable genetic variant frequencies between our cohort and reference cohorts. Out of the 154 patients included, 44.8% of patients were classified as CYP2D6 normal metabolizer, 38.3% as intermediate metabolizers, 8.4% as poor metabolizers, and 2.6% as ultrarapid metabolizers. As for CYP2C19, 40.9% of patients were classified as normal metabolizers, 19.5% as intermediate metabolizers, 2.6% as poor metabolizers, 31.2% as rapid metabolizers, and 5.8% as ultrarapid metabolizers. Approximately, 80% of patients had at least one actionable PGx variant. There is a high prevalence of actionable PGx variants in psychiatric inpatients which may affect treatment response. Physicians should refer to PGx-informed dosing guidelines in carriers of these variants. Pre-emptive PGx testing in general may facilitate precision medicine also for other drugs metabolised by CYP2D6 and/or CYP2C19. [ABSTRACT FROM AUTHOR]

Proton pump inhibitors (PPIs) are the first-line drug for eosinophilic esophagitis (EoE), although it is estimated that there is a lack of histological remission in 50% of patients. This research aimed to identify pharmacogenetic biomarkers predictive of PPI effectiveness and to study their association with disease features. Peak eosinophil count (PEC) and the endoscopic reference score (EREFS) were determined before and after an eight-week PPI course in 28 EoE patients. The impact of the signal transducer and activator of transcription 6 (STAT6), CYP2C19, CYP3A4, CYP3A5, and ABCB1 genetic variations on baseline PEC and EREFS, their reduction and histological response, and on EoE symptoms and comorbidities was analyzed. PEC reduction was higher in omeprazole-treated patients (92.5%) compared to other PPIs (57.9%, p = 0.003). STAT6 rs12368672 (g.18453G>C) G/G genotype showed higher baseline PEC values compared to G/C and C/C genotypes (83.2 vs. 52.9, p = 0.027). EREFS reduction in STAT6 rs12368672 G/G and G/C genotypes was higher than in the C/C genotype (36.7% vs. −75.0% p = 0.011). However, significance was lost after Bonferroni correction. Heartburn incidence was higher in STAT6 rs167769 (g.27148G>A) G/G patients compared to G/A (54.55% vs. 11.77%, p = 0.030). STAT6 rs12368672G>C and rs167769G>A variants might have a relevant impact on EoE status and PPI response. Further research is warranted to clarify the clinical relevance of these variants. [ABSTRACT FROM AUTHOR]

Genotype based personalized antiplatelet therapy in the setting of percutaneous coronary intervention (PCI) has been studied in clinical trials. Despite the demonstrated risk associated with CYP2C19 loss-of-function (LoF) carriage in clopidogrel-treated PCI patients, real-world implementation of genotyping for PCI has been low. The goal of the current study was to provide CYP2C19 genotype information to the interventionalist prior to the completion of the catheterization to facilitate immediate personalized antiplatelet therapy. Routine personalization of P2Y12 inhibitor therapy for PCI in a community hospital cardiac catheterization laboratory by POC genotyping with the SpartanRx system was first offered in February 2017. A best practice advisory (BPA) based on the Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 genotype and clopidogrel therapy was placed in the electronic health record prescription medication ordering system. By December 2019, 1,052 patients had CYP2C19 genotype testing, 429 patients underwent PCI with genotype guided antiplatelet therapy, and 250 patients underwent PCI without genotype testing and received antiplatelet therapy at the discretion of the treating physician. BPA compliance was 93. 87% of LoF allele carriers were prescribed ticagrelor or prasugrel whereas 96% of non-LoF allele carriers were prescribed clopidogrel. The genotyping results were available within 1 h and made immediately available for decision making by the interventional cardiologist. POC CYP2C19 genotyping is feasible in a community hospital catheterization laboratory and is associated with high rate of best practice compliance. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03040622 [ABSTRACT FROM AUTHOR]

The case discussion demonstrates the benefit of using Pharmacogenomic (PGx) results to aid in the selection of antidepressant therapy and improve response to treatment. Nearly half of patients diagnosed with major depressive disorder fail initial therapy and may require multiple trials of antidepressants. Genetic variation in several metabolic enzymes contribute to the variable response to antidepressant therapy. PGx testing provides an opportunity to inform antidepressant selection and optimize therapeutic outcomes, while minimizing risk of adverse events. A 79-year-old female who had been experiencing a suboptimal response to escitalopram following dose escalation over a period of three years was referred for a PGx consultation. A clinical pharmacist assessed significant drug-gene, drug-drug, and drug-drug-gene interactions, and relevant clinical information to recommend alternative antidepressant therapy, which resulted in mood improvement. [ABSTRACT FROM AUTHOR]

Objectives: Treatment-emergent sexual dysfunction is frequently reported by individuals with major depressive disorder (MDD) on antidepressants, which negatively impacts treatment adherence and efficacy. We investigated the association of polymorphisms in pharmacokinetic genes encoding cytochrome-P450 drug-metabolizing enzymes, CYP2C19 and CYP2D6, and the transmembrane efflux pump, P-glycoprotein (i.e., ABCB1), on treatment-emergent changes in sexual function (SF) and sexual satisfaction (SS) in the Canadian Biomarker Integration Network in Depression 1 (CAN-BIND-1) sample. Methods: A total of 178 adults with MDD received treatment with escitalopram (ESC) from weeks 0–8 (Phase I). At week 8, nonresponders were augmented with aripiprazole (ARI) (i.e., ESC + ARI, n = 91), while responders continued ESC (i.e., ESC-Only, n = 80) from weeks 8–16 (Phase II). SF and SS were evaluated using the sex effects (SexFX) scale at weeks 0, 8, and 16. We assessed the primary outcomes, SF and SS change for weeks 0–8 and 8–16, using repeated measures mixed-effects models. Results: In ESC-Only, CYP2C19 intermediate metabolizer (IM) + poor metabolizers (PMs) showed treatment-related improvements in sexual arousal, a subdomain of SF, from weeks 8–16, relative to CYP2C19 normal metabolizers (NMs) who showed a decline, F (2,54) = 8.00, p < 0.001, q = 0.048. Specifically, CYP2C19 IM + PMs reported less difficulty with having and sustaining vaginal lubrication in females and erection in males, compared to NMs. Furthermore, ESC-Only females with higher concentrations of ESC metabolite, S-desmethylcitalopram (S-DCT), and S-DCT/ESC ratio in serum demonstrated more decline in SF (r = −0.42, p = 0.004, q = 0.034) and SS (r = −0.43, p = 0.003, q = 0.034), respectively, which was not observed in males. ESC-Only females also demonstrated a trend for a correlation between S-DCT and sexual arousal change in the same direction (r = −0.39, p = 0.009, q = 0.052). Conclusions: CYP2C19 metabolizer phenotypes may be influencing changes in sexual arousal related to ESC monotherapy. Thus, preemptive genotyping of CYP2C19 may help to guide selection of treatment that circumvents selective serotonin reuptake inhibitor-related sexual dysfunction thereby improving outcomes for patients. Additionally, further research is warranted to clarify the role of S-DCT in the mechanisms underlying ESC-related changes in SF and SS. This CAN-BIND-1 study was registered on clinicaltrials.gov (Identifier: NCT01655706) on 27 July 2012. [ABSTRACT FROM AUTHOR]

Objective With the recent reports of additional alleles of the CYP2C19 gene with decreased or no function, the clinical utility of real-time polymerase chain reaction (PCR)-based testing that detects only a small number of variant targets needs to be evaluated. Method We retrospectively reviewed 7-year data for real-time PCR test records from a single hospital and analyzed CYP2C19 genotypes from publicly available whole-genome or whole-exome data from a healthy Korean population. Results Of the 2327 test results in this hospital, the *1 allele was most common (60.5%), followed by *2 (28.0%), *3 (10.1%), and *17 (1.4%). Among 5305 healthy Korean individuals, the frequencies of the *2, *3, and *17 alleles were 28.6%, 9.9%, and 1.0%, respectively, which were not statistically different from those of the hospital data (P =.4439, P =.6025, and P =.1142, respectively). Interestingly, the total frequency of additional nonfunctional alleles (*4, *6, *22, and *24) that could not be detected using real-time PCR was only 0.1%, with a total allele count of 8. Conclusion Our study shows that the clinical utility of real-time PCR for CYP2C19 genotyping remains satisfactory. However, caution should be exercised because the test can miss patients with decreased CYP2C19 function. [ABSTRACT FROM AUTHOR]

Background Cytochrome P450 2C19 (CYP2C19) intermediate and poor metabolizer patients exhibit diminished clopidogrel clinical effectiveness after percutaneous coronary intervention (PCI). However, outcome studies to date have lacked racial diversity. Thus, the impact of CYP2C19 genotype on cardiovascular outcomes in patients treated with clopidogrel who identify as Black or African American remains unclear. Methods and Results Adults among 5 institutions who self‐identified as Black or African American, underwent PCI and clinical CYP2C19 genotyping, and were treated with clopidogrel were included. Data were abstracted from health records. Major atherothrombotic (composite of death, myocardial infarction, ischemic stroke, stent thrombosis, or revascularization for unstable angina) and bleeding event rates within 1 year after PCI were compared across CYP2C19 metabolizer groups using multivariable Cox regression adjusted for potential confounders and baseline variables meeting a threshold of P

Abstract Background Clopidogrel is a widely prescribed prodrug that requires activation via specific pharmacogenes to exert its anti-platelet function. Genetic variations in the genes encoding its transporter, metabolizing enzymes, and target receptor lead to variability in its activation and platelet inhibition and, consequently, its efficacy. This variability increases the risk of secondary cardiovascular events, and therefore, some variations have been utilized as genetic biomarkers when prescribing clopidogrel. Methods Our study examined clopidogrel-related genes (CYP2C19, ABCB1, PON1, and P2Y12R) in a cohort of 298 healthy Emiratis individuals. The study used whole exome sequencing (WES) data to comprehensively analyze pertinent variations of these genes, including their minor allele frequencies, haplotype distribution, and their resulting phenotypes. Results Our data shows that approximately 37% (n = 119) of the cohort are likely to benefit from the use of alternative anti-platelet drugs due to their classification as intermediate or poor CYP2C19 metabolizers. Additionally, more than 50% of the studied cohort exhibited variants in ABCB1, PON1, and P2YR12 genes, potentially influencing clopidogrel’s transport, enzymatic clearance, and receptor performance. Conclusions Recognizing these alleles and genotype frequencies may explain the clinical differences in medication response across different ethnicities and predict adverse events. Our findings underscore the need to consider genetic variations in prescribing clopidogrel, with potential implications for implementing personalized anti-platelet therapy among Emiratis based on their genetic profiles.

Background: Potentially substantial impacts on the prognosis have been observed in individuals undergoing endovascular treatment due to cytochrome P450 2c19 (CYP2C19) polymorphism. In an attempt to improve prognosis and lower the recurrence rate, this study investigated the CYP2C19 polymorphism in acute ischemic stroke patients. Materials and Methods: A retrospective analysis was performed on 292 patients with cerebral infarction who had acute endovascular recanalization at the Department of Neurology of Chongqing Hospital of Traditional Chinese Medicine between May 2017 and 2019. The patients were categorized into rapid-, medium-, and slow-metabolism groups based on CYP2C19 gene polymorphism, and their prognosis was monitored. In addition, the prognosis of 188 patients selectively receiving carotid artery stenting at a selected time was also observed. Results: Among the 292 cerebral infarction cases receiving acute endovascular recanalization, the patients in the CYP2C19 rapid-metabolism group regularly took clopidogrel and aspirin combined with antiplatelet therapy and suffered from reoccurrence of apoplexy and cerebral hemorrhage; the 90-day good prognosis had a statistical difference (P < 0.05, prognostic assessment includes hospitalization and 6 months after discharge) and the other adverse events had no statistical difference (including mortality). The 188 patients selectively receiving carotid artery stenting had a recurrence of apoplexy, cerebral hemorrhage, and restenosis rate with a statistical difference (P < 0.05), and the other adverse events had no statistical difference. Conclusions: In conclusion, the findings of the current study indicate that irrespective of whether patients are undergoing selective carotid artery stenting or acute endovascular recanalization, those with rapid CYP2C19 metabolism have a significantly lower likelihood of experiencing adverse prognostic events compared to those with intermediate and slow metabolism. Furthermore, this group also has a more favorable prognosis than the other two groups.