Voriconazole is commonly used to prevent fungal infections after haematopoietic stem cell transplantation (HSCT). Although its metabolism is influenced by CYP2C19 genetics and inflammation, their combined effect is rarely considered in clinical practice, and integrated analyses remain limited. We retrospectively analysed how inflammation and CYP2C19-predicted drug-metaboliser phenotypes affect voriconazole exposure and therapeutic range attainment in 126 HSCT patients. C-reactive protein (CRP) ≥ 10mg/L defined inflammation. A linear mixed model (LMM) assessed associations between dose-corrected voriconazole concentrations, inflammation and CYP2C19-predicted drug-metaboliser phenotype. Dose-corrected voriconazole trough concentrations were associated with CYP2C19-predicted drug-metaboliser phenotype (LMM p = <2e-16, effect size of CYP2C19-phenotype: β = -5.99e-02-mg/L per mg voriconazole, standard error (SE) = 2.75e-02-mg/L per mg voriconazole, p = 0.0315; effect size of CRP: β = 1.54e-03-mg/L per mg voriconazole, SE = 2.79E-04-mg/L per mg voriconazole, p = 5.49e-08) and were higher during inflammation. Inflammation increased supra-therapeutic concentrations and reduced subtherapeutic levels (p = 0.0080). This effect was most pronounced for intermediate metabolisers (n = 18 with and n = 31 without inflammation) and rapid metabolisers (n = 20 with and n = 28 without inflammation), with supra-therapeutic concentration of 33% vs. 3%, and 15% vs. 0%, respectively (p = 0.02). Finally, in a longitudinal subset (n = 25), concentrations tracked inflammatory status across prior-, during and post-inflammation timepoints. This study demonstrates inflammation and CYP2C19 genotype jointly influence voriconazole exposure and target attainment in clinical practice. These findings support intensified therapeutic drug monitoring with concurrent CRP assessment, particularly for intermediate and rapid metabolisers, to reduce the risk of supra-therapeutic voriconazole concentrations during inflammation.

Clinical relevance of CYP2C19 genetic polymorphisms in real-world patient populations requires further investigation. This study aimed to determine the prevalence of CYP2C19 genetic variants in patients with GORD showing resistance to PPI therapy and possible clinical implications. Patients with GORD and documented PPI resistance were identified from ambulatory reflux monitoring and endoscopy databases. EDTA blood samples were obtained for CYP2C19 genotyping using real-time polymerase chain reaction and reverse hybridisation. Genotypes (phenotypes) were categorised into: *1/*1 (normal metabolisers, NMs), *1/*17 (rapid metabolisers, RMs), *17/*17 (ultra-rapid metabolisers, UMs), *1/*2, *2/*17 (intermediate metabolisers, IMs), *2/*2 (poor metabolisers,PMs). Fifty patients were assessed (49 European ancestry, 28 male, modal age 50-59 years). Predominant resistance patterns included reflux hypersensitivity (n=19) and persistent oesophagitis (n=17). PPI therapy included esomeprazole (n=26), omeprazole (n=22), lansoprazole (n=2). Genotyping identified 26 NMs (52 %), 8 RMs (16 %), 14 IMs (28 %), 2 PMs (4 %); no UMs were identified. Findings from this preliminary study indicate a higher frequency of NMs and RMs compared to IMs and PMs in this PPI-resistant cohort with GORD. Most resistance was observed to the second-generation PPI esomeprazole. A limitation was the lack of a control group comprising PPI-sensitive patients.

CYP2C19 genotyping and mavacamten: predicting outcomes in normal, intermediate and rapid metabolisers in obstructive hypertrophic cardiomyopathy.

Warfarin remains one of the most widely used anticoagulants; however, its narrow therapeutic index means that even small dosing deviations can result in thromboembolic or bleeding events, necessitating close monitoring and strict control of the international normalized ratio (INR). Although traditional warfarin dosing algorithms incorporating CYP2C9 and VKORC1 genotypes improve upon fixed-dose regimens, they explain less than 50% of dose variability and perform inconsistently across populations. These limitations underscore the need for more adaptive and precise dosing methodologies. Artificial intelligence (AI) and machine learning (ML) have been recognized as powerful approaches to advance warfarin dose individualization. This narrative review synthesizes literature on machine learning approaches to warfarin dosing, including support vector regression, neural networks, ensemble models, and reinforcement learning, with a focus on predictive performance and clinical relevance. Overall, the literature indicates that ML-based warfarin dosing models may improve prediction of the therapeutic warfarin dose and regulation of INR levels compared with traditional clinical and pharmacogenetic interventions. However, many published models are constrained by small sample sizes and limited external validation, reducing generalizability. Methodological heterogeneity and inconsistent reporting further underscore persistent gaps in the evidence base. AI and ML approaches have shown potential advantages over clinical and pharmacogenetic dosing methods for warfarin, with some studies reporting lower prediction errors and improved therapeutic INR control. However, further studies are needed to draw definitive conclusions about their comparative effectiveness.

Impact of Area-Level Socioeconomic Deprivation on Post-PCI Outcomes Stratified by P2Y12 Inhibitor Therapy.

Implementing CYP2C19 Pharmacogenetic Testing for Personalized Antiplatelet Therapy: Findings From the QPGx-CARES Initiative.

Voriconazole (VRC), a triazole antifungal agent, is recommended as primary treatment for invasive aspergillosis. Due to its unpredictable dose-exposure relationship, therapeutic drug monitoring (TDM) is recommended. Despite TDM, the probability of achieving therapeutic targets is only approximately 50%. This highlights the need for new dosing strategies. Calculating the metabolic ratio (MR) of NOX, the principal N-oxide metabolite of voriconazole primarily formed by the genetically polymorphic CYP2C19 enzyme, to VRC concentrations could serve as a surrogate for phenotype information. This is particularly relevant since the CYP2C19 genotype is often unavailable in acute clinical settings. Moreover, genotype may be less informative during inflammation due to a phenomenon known as 'phenoconversion', where inflammation masks genotype effects through downregulation of CYP450 enzymes. However, before integrating NOX in population PK models and/or as an adjunct in voriconazole TDM flowcharts, it is important to understand the factors impacting NOX exposure, and hence the MR. The objective of this narrative review is therefore to summarise recent literature on patient- and drug-related covariates impacting NOX exposure. A comprehensive search was conducted in PubMed and Embase for articles published from 2003 to 2025 focusing on factors impacting NOX or the MR. Twenty-one articles were included, predominantly involving adult patients from an Asian or white ethnicity. Studies were mainly set up as pharmacokinetic (PK) studies, in which associations between NOX or MR were assessed in uni- or multivariate analyses. Key covariates identified were as follows: (1) voriconazole dose (6/11 studies)-higher doses increasing NOX, although this relationship was complicated by saturated metabolism; (2) C-reactive protein (CRP) (8/9)-higher inflammation levels correlated with reduced metabolic capacity due to CYP450 enzyme downregulation; (3) age (7/12)-children exhibited higher MR, probably driven by higher clearance due to increased CYP2C19 and FMO3 expression, while older adults (> 60 years) showed decreased MR due to a decline in CYP2C19 activity; (4) CYP2C19 genotype (10/13)-poor metabolizers had lower MR and lower NOX, supporting the utility of genotyping, if available with acceptable turnaround time. A CRP threshold of 100 mg/L has been found in some studies and may serve as a crucial indicator for clinicians in optimising dosage adjustments. Although hepatic impairment is recognised as a significant covariate for voriconazole, its influence on NOX or the MR was found limited in this review. This is likely due to the exclusion of patients with hepatic impairment from most studies, which resulted in lower interindividual variation in liver function test results. While renal function does not affect voriconazole exposure, it may impact NOX or MR, as some studies suggest a higher renal clearance of NOX compared to voriconazole. However, only one of the included studies suggested that impaired renal function resulted in a higher MR, indicating NOX accumulation. Further research is however needed. VRC dose, CRP, age and CYP2C19 genotype are the primary covariates affecting NOX or MR, and renal and liver function should also be considered in future population pharmacokinetic models and TDM protocols.

Background:While recipient cytochrome P450 (CYP) genetic polymorphisms are established modulators of tacrolimus (TAC) pharmacokinetics, the combined effects of donor-derived hepatic and recipient intestinal CYP3A4/5 and CYP2C19 genotypes during voriconazole (VRC)-mediated CYP3A inhibition remain inadequately elucidated in liver transplantation.Objectives:This study evaluated the impact of donor and recipient CYP3A4/5 and CYP2C19 polymorphisms on TAC pharmacokinetics during VRC co-therapy in liver transplant recipients.Design:A retrospective study was conducted on 139 liver transplant patients receiving TAC-based immunosuppressive therapy at the First Affiliated Hospital of Sun Yat-sen University from December 2016 to June 2025.Methods:The liver transplant recipients were stratified into a VRC co-therapy group (n = 33) and a non-VRC control group (n = 106). TAC dose-corrected trough concentrations (C0/D) were analyzed in relation to donor and recipient genotypes of CYP3A4*1G (rs2242480), CYP3A5*3 (rs776746), CYP2C19*2 (rs4244285), and CYP2C19*3 (rs4986893).Results:During VRC co-therapy, dual donor-recipient CYP3A4*1G CC carriers exhibited a 73% increase in TAC C0/D compared with TT/TC genotypes (6.83 vs 3.95, p = 0.0031). Recipients grafted from CYP3A5 non-expresser donors exhibited 34% higher TAC C0/D than those from CYP3A5 expressers (6.35 vs 4.75, p = 0.0196). Recipient CYP2C19 poor metabolizers demonstrated 36% elevated TAC C0/D compared to extensive or intermediate metabolizers (6.47 vs 4.76, p = 0.0401). The magnitude of TAC-VRC interaction was modulated by both donor and recipient genotypes. Comparing with the control group, VRC co-therapy increased TAC C0/D by 3.80- and 2.75-fold increases in CYP3A5 expresser and non-expresser recipients, respectively, and by 3.44- and 3.53-fold in recipients grafted from CYP3A5 expresser and non-expresser donors, respectively. Post-VRC discontinuation, TAC C0/D remained significantly elevated for 5 days before returning to baseline level by day 6 (p < 0.0001).Conclusion:In summary, Donor and recipient CYP3A4/5 and CYP2C19 genotypes jointly influence TAC pharmacokinetics during VRC co-therapy. Genotype-guided dosing strategies integrating both donor and recipient genotypes may improve TAC dosing precision. TAC dose reinstatement may be deferred until day six following VRC discontinuation to avoid overexposure.

Background: CYP2C19 is required to metabolize clopidogrel into its active form to inhibit adenosine diphosphate (ADP) platelet aggregation. Variability in patient response to clopidogrel is driven by CYP2C19 genetic polymorphisms. Abnormal metabolism has been shown to result in increased recurrent ischemic events. The purpose of this study was to examine CYP2C19 phenotypes and the impact on ADP aggregation in whole blood platelet aggregometry (WBPA) in acute stroke patients. Methods: We retrospectively reviewed electronic medical records of patients who presented to two academic Comprehensive Stroke Centers and discharged with acute ischemic stroke (AIS) or transient ischemic attack (TIA) from 1/1/2022 to 5/31/2025. Patients were included if they had AIS/TIA, WBPA, and CYP2C19 genotyping. WBPA had to be performed at least 6 hours after loading clopidogrel with 300 mg dose or &gt;7 days of clopidogrel 75 mg daily. Nominal variables were examined with descriptives and frequencies. Non-parametric continuous variables were assessed by Kruskall-Wallis and Jonckheere-Terpstra was used to assess ADP aggregation by CYP2C19 phenotype. Results: We identified 115 patients (mean age 68.9±12.2 years, 68 male, 27.8% Hispanic) who met inclusion criteria. The frequency of CYP2C19 phenotype was 8 (7.0%) poor, 43 (37.4%) intermediate, 59 (51.3%) normal, and 5 (4.3%) ultrarapid metabolizers. There was no significant difference in age (p=0.38) or race (p=0.13) between phenotypes. CYP2C19 phenotypes was significantly associated with Hispanic ethnicity (p=0.001). There was no significant difference in ADP aggregation on WBPA between CYP2C19 phenotypes (p=0.58). The decision to change antiplatelet agents was significantly correlated with history of stroke (p=0.001); HTN (p=0.04); CAD (p=0.03); prior clopidogrel use (p&lt;0.001); and ADP aggregation (p=0.02). Conclusion: In this study, CYP2C19 phenotype distribution was predominantly normal or intermeditate, with no significant association between phenotype and ADP aggregation on WBPA. CYP2C19 phenotype correlated with Hispanic ethnicity, suggesting population-level variability. Antiplatelet changes were significantly associated with clinical history (stroke, HTN, CAD, prior clopidogrel use) and ADP aggregation but not with phenotype. These findings underscore the need for larger studies to clarify genetic and clinical predictors of clopidogrel metabolism in stroke patients to better inform individualized antiplatelet therapy.

Background/Objectives: Venlafaxine has been reported to exhibit significant interindividual pharmacokinetic heterogeneity across populations, which has been linked to cytochrome P450 polymorphisms and clinical factors. This study aimed to assess the impact of pharmacogenetic (PGx) and clinical determinants on the dose-normalized venlafaxine/O-desmethylvenlafaxine (ODV) metabolic ratios (MRs) in routine clinical settings in Spain. Methods: 29 adult patients receiving venlafaxine were prospectively recruited through the MedeA PGx Implementation Strategy into clinical practice (Extremadura, Spain). CYP2D6, CYP2C19, and CYP2C9 genotypes were determined using TaqMan® assays, and CYP2D6 activity scores were assigned based on allele functionality. Steady-state trough plasma concentration of venlafaxine and ODV were measured using a validated high-performance liquid chromatography method. Dose-normalized venlafaxine/ODV MRs were compared across CYP2D6-, CYP2C19-, and CYP2C9-genotype-predicted metabolizer groups. The influence of demographic and clinical variables on dose-normalized venlafaxine/ODV MR was also assessed. Results: Significant variability in dose-normalized venlafaxine/ODV MRs was observed across CYP2D6 (p = 0.019) and CYP2C19 (p = 0.008) metabolizer groups. Among clinical variables, sex was significantly associated with differences in dose-normalized venlafaxine/ODV MR (p = 0.0006). Conclusions: CYP2D6 and CYP2C19 genotypes and sex significantly contribute to variability in venlafaxine metabolism in patients treated in routine clinical settings. These results highlight the value of combining PGx and clinical data with drug plasma concentration measurement to optimize venlafaxine therapy within PGx implementation programs.

Aim. To analyse the frequencies of the CYP2C19 gene alleles and genotypes associated with the metabolism of antiplatelet agents in patients with coronary artery disease (CAD), considering potential drug-drug interactions in real clinical practice in Arkhangelsk. Material and methods. The cross-sectional study was conducted at the Emergency Cardiology Department of the Regional Vascular Center of the E.E. Volosevich First City Clinical Hospital in Arkhangelsk. The study included 96 patients diagnosed with CAD (I20.0-I22.0 according to ICD-10). Patients were divided into two groups: those hospitalized for the first time and those readmitted. All patients underwent pharmacogenetic testing of polymorphic variants of the CYP2C19 gene. Genotyping of polymorphic variants of the CYP2C19 gene was performed using the polymerase chain reaction (PCR) method in real time. The analysis of allelic variants rs28399504, rs4244285, rs4986893 of the CYP2C19 gene was performed on a Bio-Rad CFX96 Touch amplifier using the SNP-Screen kits (Synthol LLC, RF). Results. The study included 96 patients with CAD aged 39 to 100 years. The patients were divided into two groups: primarily hospitalised and patients readmitted for recurrent acute coronary syndrome. The groups were comparable in sex and age. Significant differences were observed for INR: 1.05 [1.00; 1.14] in the first group and 1.08 [1.03; 1.14] in the second group (p=0.04), as well as for treatment outcome – 4 fatal cases (10%) were noted in the second group, while all patients in the first group were discharged (p=0.016). In both groups, carriers of low-functional CYP2C19 variants (G681A, G636A), classified as intermediate or poor metabolisers, were identified in both groups, which may be significant for drug-drug interactions in CAD pharmacotherapy in clinical practice. The A1G variant was identified only in the first group (3,6% (n=2)). No statistically significant difference was found in the frequency of loss-of-function alleles between the groups or in the frequency of readmissions during antiplatelet therapy. Analysis of therapy in patients carrying pathological alleles revealed potentially adverse drug-drug interactions, e.g., clopidogrel and omeprazole, manifested as reduced clopidogrel efficacy and an increased risk of gastrointestinal bleeding. Conclusion. This study did not reveal a statistically significant association between the presence of mutant CYP2C19 gene alleles and the frequency of readmissions, but emphasized the importance of a comprehensive personalized approach to pharmacotherapy in CAD patients. Consideration of pharmacogenetic, clinical, and pharmacological factors may contribute to therapy optimization and improvement of CAD treatment outcomes. Further studies with larger samples (including population-based studies) are required for definitive conclusions.

The activity of CYP2C9, an important drug metabolism enzyme, is subject to the impact of genetic polymorphism. The single nucleotide polymorphism *3 is significantly associated with the increased exposure of CYP2C9 substrates. In addition, metabolic enzyme inhibitors such as fluconazole may also increase the drug exposure of CYP2C9 substrates. However, the interactions between the impact of CYP2C9 genotypes and the inhibitory effects of interacting drugs with respect to the CYP2C9 mediated fraction of metabolism (fm) are rarely investigated. Using tolbutamide, flurbiprofen and ketoprofen as representative substrates with high, medium and low CYP2C9 mediated fm, respectively, an open-label, block-randomized, crossover clinical drug-drug interaction study was conducted using fluconazole as a representative interacting drug. A pharmacometric model-based analysis was subsequently performed to assess the impact of CYP2C9 genotypes on the absolute and fractional changes in apparent clearance (CL/F) with fluconazole co-administration. Our study shows tolbutamide and flurbiprofen, but not ketoprofen, exhibit CYP2C9 genotype-dependency on both absolute and fractional changes in CL/F following the fluconazole co-administration. An interesting finding is the CYP2C9 genotype-dependency on fluconazole induced fractional CL/F changes is more pronounced in a CYP2C9 substrate with medium CYP2C9 mediated fm, in comparison to a CYP2C9 substrate with high or low CYP2C9 mediated fm. Our study provides quantitative insights into the genotype-dependent exposure changes of probe drugs with varying CYP2C9 metabolic contributions following the co-administration of fluconazole, highlighting the role of CYP2C9 metabolic contributions in guiding the precision dosing of CYP2C9 substrates.

Assessing the influence of CYP2C9 and CYP2C19 genotypes on the metabolism of CBD-cannabis after controlled single and repetitive consumption.

The Dutch Pharmacogenetic Working Group (DPWG) aims to integrate pharmacogenetics into clinical practice by creating evidence-based guidelines to optimize pharmacotherapy based on genetic tests. The current guideline describes the gene-drug interactions between CYP2D6 and CYP2C19 and various tricyclic antidepressants (TCAs). For CYP2D6 poor metabolisers (PM), dose reductions are advised for amitriptyline (reduction to 60% of the normal dose), clomipramine (reduction to 50% of the normal dose for the indication depression or in case of side effects at the normal dose for the other indications), doxepin (reduction to 40% of normal dose), imipramine (30% of the normal dose), and nortriptyline (40%). For CYP2D6 intermediate metabolisers (IM) reduced dose is also recommended for amitriptyline (75%), clomipramine (70%), doxepin (80%), imipramine (70%), and nortriptyline (60%). Also, CYP2D6 ultra-rapid metabolisers (UM) require tailored dose adjustments: amitriptyline (1.6 times the normal dose), clomipramine (1.5 times), doxepin (2 times), imipramine (1.7 times), and nortriptyline (1.7 times). Additionally, alternative drugs may be needed for CYP2D6 UM due to potential safety concerns. For CYP2C19 PM, a 70% dose reduction is advised for imipramine. For CYP2C19 IM, no action is required for TCAs. For CYP2C19 UM, an alternative medication is recommended for clomipramine prescribed for anxiety and obsessive-compulsive disorder (OCD). The DPWG classifies CYP2D6 genotyping for all five TCAs and CYP2C19 genotyping for clomipramine in patients with anxiety disorders or OCD, and for imipramine as being "potentially beneficial". Genotyping prior to treatment can be considered on an individual patient basis.

Helicobacter pylori antimicrobial resistance and CYP2C19 genotypes in a paediatric cohort with initial eradication failure: A study from Henan, China (2019-2024).

Dual antiplatelet therapy guided by CYP2C19 polymorphism after intracranial or extracranial stenting: A single-center retrospective cohort study.

Genetic Determinants of Response to P2Y12 Inhibitors and Clinical Implications.

Abstract Background Prognostic markers of response to tofacitinib (TFB) are lacking in ulcerative colitis (UC). Multidrug resistance protein (MDR) activity, alterations in metabolism via cytochrome-P450 (CYP) isoenzymes, mucosal change of JAK/STAT signalling pathways may predict treatment response. Methods We enrolled adult UC patients before introducing TFB treatment and followed them until w12. At baseline we measured the activity of three ABC drug transporters (MDR1, MRP1, and BCRP) in leukocytes. Patients’ tofacitinib-metabolizing capacity was characterized by CYP2C19, CYP3A5 and CYP3A4 genotypes. Clinical parameters were registered, while colonoscopy examinations were performed at baseline and at w12. Mucosal sampling was also performed to measure mucosal cytokine levels (e.g. TNF-α, PAI-1) and alterations in JAK/STAT gene expressions. W12 corticosteroid-free remission (CSFR) and endoscopic remission/response, histological remission (HR) and treatment persistence were used as outcomes. We performed multivariable logistic regression models on these specific outcomes and data was handled with intention-to-treat analysis. Results In total, we included 63 patients (male/female ratio 24/39; mean age 38.7±11.7 years; mean Mayo score 8.9±2.4) in our study. In total, 7 patients (9.2%) achieved HR, while 20 patients (26.7%) achieved endoscopic remission, and 27 patients (42.9%) endoscopic response. Clinical remission was observed in 21 patients (33.3%), while clinical response was achieved by 30 patients (47.6%). In total, 34 patients (54.0%) were in CSFR at w12, and higher baseline pMayo score decreased (OR = 0.64 [95% CI:0.43–0.94]), while albumin increased (OR = 1.33 [95% CI:1.01–1.76]) the chance of achieving the outcome (AUC = 0.93). We found that one-year treatment persistence was strongly influenced by week 12 endoscopic remission (β = 3.79 [95% CI:1.21–6.37]), but not by histological remission (β = 1.58 [95% CI:-0.74–3.89]). Higher baseline CD8⁺ MDR1 activity decreased the chance of clinical response (OR = 0.91; p = 0.048), while higher CD8⁺ MRP1 decreased week 12 treatment persistence (r = 0.32). CYP3A5 1/3 genotype increased the histological remission rates (OR = 13.9 [95% CI:1.04-186.2]). The levels of mucosal IL-6 (18.51 vs 25.72 pg/mg, p = 0.049), IL-4 (94.41 vs 168.8 pg/mg, p = 0.037) and PAI-1 (921 vs 1483 pg/mg, p = 0.01) were significantly lower in the clinical/endoscopic responders at the baseline. Conclusion Based on our prospective cohort study, short-term histological remission is still a hard-to-reach endpoint in moderate-to-severe UC on TOFA. Measurement of baseline CD8⁺ MRP1 and CD8⁺ MDR1 activity, and mucosal levels of IL-1β, IL-6, IL-4, and PAI-1, and CYP3A5 genotype may help to increase treatment success. Conflict of interest: Dr. Resál, Tamás: Jójárt, Boldizsár: I have no conflict of interest. Bacsur, Péter: No conflict of interest Kajári, Lilian: No conflict of interest Molnár, Tünde: No conflict of interest Balázs, Hallgas: No conflict of interest Tímea, Pintér: No conflict of interest Kovács, Blanka: No conflict of interest Éva, Kárpáti: No conflict of interest Katalin, Monostory: No conflict of interest Farkas, Bernadett: No conflict of interest Ivány, Emese: No conflict of interest Bálint, Anita: No conflict of interest Fábián, Anna: No conflict of interest Bor, Renáta: No conflict of interest Rutka, Mariann: No conflict of interest Szepes, Zoltán: No conflict of interest Farkas, Klaudia: No conflict of interest József, Maléth: No conflict of interest Molnár, Tamás: No conflict of interest

Black individuals undergoing percutaneous coronary intervention (PCI) experience higher rates of major adverse cardiovascular events (MACE) than non-Black individuals. This study assessed the racial differences in platelet reactivity and clinical outcomes among clopidogrel-treated participants. Two cohorts were analyzed. The pharmacodynamic (PD) cohort involved patients with atherosclerotic cardiovascular disease on maintenance clopidogrel therapy undergoing platelet function testing. The primary outcome was high platelet reactivity (HPR, i.e., P2Y12 reaction unit [PRU] > 208). The PCI cohort included participants undergoing PCI on clopidogrel-based dual antiplatelet therapy. The primary outcome was 1-year MACE, defined as the composite of cardiovascular death, myocardial infarction (MI), ischemic stroke, or stent thrombosis. Data on clinically significant bleeding and CYP2C19 genotyping alleles were collected. The PD and PCI cohorts included 728 (32.1% Black) and 2,770 (20.5% Black) participants, respectively. Black participants had higher PRU levels (184 [IQR 128-234] vs. 144 [IQR 88-195]; P < 0.001) and higher prevalence of HPR (39.3% vs. 20.6%; P < 0.001). Independent predictors of HPR included Black race, hemoglobin levels, and presence of CYP2C19 loss-of-function allele. In the PCI cohort, Black participants had a higher risk of MACE (HR 1.47; 95% CI 1.02-2.11; P = 0.037), primarily driven by MI (HR 1.71; 95% CI 1.09-2.67; P = 0.019), with no significant difference in clinically significant bleeding (HR 1.08; 95% CI 0.65-1.80; P = 0.768). Black participants on clopidogrel exhibit higher platelet reactivity, increased rates of HPR, and an elevated risk of MACE within 1 year after PCI, without significant differences in bleeding compared to non-Black participants.

Background: Fluoxetine, a widely prescribed selective serotonin reuptake inhibitor, exhibits significant interindividual variability in pharmacokinetics, largely attributed to pharmacogenomic factors. Objectives: The study aimed to evaluate the impact of pharmacogenetics and clinical determinants on the dose-normalized fluoxetine/norfluoxetine metabolic ratio in patients undergoing fluoxetine therapy in routine clinical settings. Methods: Genotypes for CYP2D6, CYP2C9, and CYP2C19 genotypes were determined in 47 patients receiving fluoxetine therapy using TaqMan® assays. Steady-state trough plasma concentrations of fluoxetine and norfluoxetine were measured using validated high-performance liquid chromatography methods. Log10-transformed dose-normalized fluoxetine/norfluoxetine metabolic ratio (logMR) was compared across CYP2D6, CYP2C9, and CYP2C19 genotype-predicted metabolizer groups. Multivariate generalized linear modeling (GLM) was used to evaluate the independent effects of CYP genotypes and clinical covariates on the logMR. Results: The logMR differed significantly among the CYP2D6 genotype-predicted metabolizer groups (p < 0.003). CYP2D6 poor metabolizers exhibited significantly higher logMR than normal metabolizers (p < 0.004). The GLM analysis confirmed that CYP2D6 genotype was the only significant predictor of the logMR independent of all clinical covariates. No significant effects of CYP2C9, CYP2C19 genotypes, or clinical variables on the logMR were observed. Conclusions: These findings highlight CYP2D6 genotype as a key determinant of fluoxetine metabolism during standard treatment. No associations were observed with CYP2C9 or CYP2C19 genotypes or clinical factors.