Post-percutaneous coronary intervention CYP2C19 genotyping in an Irish population: The potential role in identifying clopidogrel therapy-related bleeding risks.

AIMS: Dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) remains the standard of care. CYP2C19 genetic polymorphisms cause variable clopidogrel bioactivation. Increased function (CYP2C19*17) allele carriers (rapid metabolizers [RM] or ultrarapid metabolizers [UM]) are clopidogrel hyper-responders, hence are more susceptible to clopidogrel-related bleeding. Since current guidelines recommend against routine genotyping following PCI, data on the clinical utility of CYP2C19*17 genotype guided strategy are sparce. Our study provides real-world data on the 12-month follow-up of CYP2C19 genotyping in patients post-PCI. METHODS: This is a cohort study within an Irish population receiving 12-month DAPT following PCI. It identifies the prevalence of CYP2C19 polymorphisms within an Irish population and describes the ischaemic and bleeding outcomes after 12 months of DAPT. RESULTS: A total of 129 patients were included with the following CYP2C19 polymorphism prevalence: 30.2% hyper-responders (26.4% RM [1*/17*], 3.9% UM [17*/17*]) and 28.7% poor-responders (22.5% IM [1*/2*], 3.9% IM [2*/17*], 2.3% PM [2*/2*]). A total of 53 and 76 patients received clopidogrel and ticagrelor, respectively. At 12 months, total bleeding incidence within the clopidogrel group was positively correlated with CYP2C19 activity: IM/PM (0.0%), NM (15.0%) and RM/UM (25.0%). The positive relationship showed a moderate association that was statistically significant: rτ = 0.28, P = 0.035. CONCLUSIONS: The prevalence of CYP2C19 polymorphisms in Ireland is 58.9% (30.2% CYP2C19*17, 28.7% CYP2C19*2) with an approximately one in three chance of being a clopidogrel hyper-responder. Positive correlation between bleeding and increasing CYP2C19 activity within the clopidogrel group (n = 53) suggests possible clinical utility of a genotype-guided strategy identifying high bleeding risk with clopidogrel in CYP2C19*17 carriers, but further studies are required.

Prediction of Omeprazole Pharmacokinetics and its Inhibition on Gastric Acid Secretion in Humans Using Physiologically Based Pharmacokinetic-Pharmacodynamic Model Characterizing CYP2C19 Polymorphisms.

PURPOSE: To develop a whole physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model to describe the pharmacokinetics and anti-gastric acid secretion of omeprazole in CYP2C19 extensive metabolizers (EMs), intermediate metabolizers (IMs), poor metabolizers (PMs) and ultrarapid metabolizers (UMs) following oral or intravenous administration. METHODS: A PBPK/PD model was built using Phoenix WinNolin software. Omeprazole was mainly metabolized by CYP2C19 and CYP3A4 and the CYP2C19 polymorphism was incorporated using in vitro data. We described the PD by using a turn-over model with parameter estimates from dogs and the effect of a meal on the acid secretion was also implemented. The model predictions were compared to 53 sets of clinical data. RESULTS: Predictions of omeprazole plasma concentration (72.2%) and 24 h stomach pH after administration (85%) were within 0.5-2.0-fold of the observed values, indicating that the PBPK-PD model was successfully developed. Sensitivity analysis demonstrated that the contributions of the tested factors to the plasma concentration of omeprazole were Vmax,2C19 ≈ Papp > Vmax,3A4 > Kti, and contributions to its pharmacodynamic were Vmax,2C19 > kome > kms > Papp > Vmax,3A4. The simulations showed that while the initial omeprazole dose in UMs, EMs, and IMs increased 7.5-, 3- and 1.25-fold compared to those of PMs, the therapeutic effect was similar. CONCLUSIONS: The successful establishment of this PBPK-PD model highlights that pharmacokinetic and pharmacodynamic profiles of drugs can be predicted using preclinical data. The PBPK-PD model also provided a feasible alternative to empirical guidance for the recommended doses of omeprazole.

Clinical impact of high platelet reactivity in patients with atrial fibrillation and concomitant percutaneous coronary intervention on dual or triple antithrombotic therapy.

High platelet reactivity (HPR) on clopidogrel is an established thrombotic risk factor after percutaneous coronary intervention (PCI). The introduction of more potent antiplatelet drugs has partially surpassed this issue. However, in the setting of concomitant atrial fibrillation (AF) and PCI clopidogrel is still the most adopted P2Y12 inhibitor. In the present study all consecutive patients with history of AF discharged from our cardiology ward with dual (DAT) or triple (TAT) antithrombotic therapy after a PCI from April 2018 to March 2021 were enrolled in an observational registry. For all subjects, blood serum samples were collected and tested for platelet reactivity by arachidonic acid and ADP (VerifyNow system) and genotyping of the CYP2C19*2 loss-of-function polymorphism. We recorded at 3 and 12-months follow-up: (1) major adverse cardiac and cerebrovascular events (MACCE), (2) major hemorrhagic or clinically relevant non-major bleeding and (3) all-cause mortality. A total of 147 patients were included (91, 62% on TAT). In 93.4% of patients, clopidogrel was chosen as P2Y12 inhibitor. P2Y12 dependent HPR resulted an independent predictor of MACCE both at 3 and 12 months (HR 2.93, 95% C.I. 1.03 to 7.56, p = 0.027 and HR 1.67, 95% C.I. 1.20 to 2.34, p = 0.003, respectively). At 3-months follow-up the presence of CYP2C19*2 polymorphism was independently associated with MACCE (HR 5.21, 95% C.I. 1.03 to 26.28, p = 0.045). In conclusion, in a real-world unselected population on TAT or DAT, the entity of platelet inhibition on P2Y12 inhibitor is a potent predictor of thrombotic risk, suggesting the clinical utility of this laboratory evaluation for a tailored antithrombotic therapy in this high-risk clinical scenario. The present analysis was performed in patients with AF undergoing PCI on dual or triple antithrombotic therapy. At 1 year follow-up MACCE incidence was consistent, and it was not different in different antithrombotic pattern groups. P2Y12 dependent HPR was a potent independent predictor of MACCE both at 3- and 12-months follow-up. In the first 3 months after stenting the carriage of CYP2C19*2 allele was similarly associated with MACCE. Abbreviation: DAT, dual antithrombotic therapy; HPR, high platelet reactivity; MACCE, major adverse cardiac and cerebrovascular events; PRU, P2Y12 reactive unit; TAT, triple antithrombotic therapy. Created with BioRender.com.

Pharmacokinetic and Adsorptive Analyses of Administration of Oral Voriconazole Suspension via Enteral Feeding Tube in Intensive Care Unit Patients.

For intensive care unit (ICU) patients, injectable voriconazole (VRCZ) is difficult to use because the patients often develop acute kidney injury. Since many ICU patients have consciousness disturbance, oral ingestion of tablet formulation is also difficult, and administration of a suspension via enteral feeding tube is required when using VRCZ. In this study, we investigated the in vitro adsorption property of oral VRCZ to feeding tube and performed pharmacokinetic analysis of VRCZ prepared by powdering and simple suspension for ICU patients. VRCZ was tube-administered to five ICU patients at a loading dose of 300 mg and plasma VRCZ concentrations before and at 1, 2, 4, 8, 12 h after the first dose were measured using HPLC. Pharmacokinetic parameters were calculated by non-compartmental model analysis. The recovery rate of VRCZ after infusion of the suspension through feeding tube was 89.8 ± 8.3%, but the cumulative rates after the first and second re-infusion were 102.7 ± 20.7 and 99.3 ± 10.3%, respectively, suggesting almost no residual drug in the tube after re-infusion. Metabolic phenotype was extensive metabolizer (EM) in two patients and intermediate metabolizer (IM) in three patients. The values of total clearance (CLtot/F) calculated by moment analysis were 0.51 and 0.55 L/h/kg in two EM patients, and 0.09, 0.29 and 0.31 L/h/kg in three IM patients. The CLtot/F was apparently lower in IM patients compared to EM. In conclusion, powdered and suspended VRCZ administered via enteral feeding tube showed pharmacokinetics depending on CYP2C19 gene polymorphism, similar to that observed in usual oral administration.

The Role of Genetic Polymorphism and Other Factors on Clopidogrel Resistance (CR) in an Asian Population with Coronary Heart Disease (CHD).

Clopidogrel is a widely-used antiplatelet drug. It is important for the treatment and prevention of coronary heart disease. Clopidogrel can effectively reduce platelet activity and therefore reduce stent thrombosis. However, some patients still have ischemic events despite taking the clopidogrel due to the alteration in clopidogrel metabolism attributable to various genetic and non-genetic factors. This review aims to summarise the mechanisms and causes of clopidogrel resistance (CR) and potential strategies to overcome it. This review summarised the possible effects of genetic polymorphism on CR among the Asian population, especially CYP2C19 *2 / *3 / *17, where the prevalence rate among Asians was 23.00%, 4.61%, 15.18%, respectively. The review also studied the effects of other factors and appropriate strategies used to overcome CR. Generally, CR among the Asian population was estimated at 17.2-81.6%. Therefore, our overview provides valuable insight into the causes of RC. In conclusion, understanding the prevalence of drug metabolism-related genetic polymorphism, especially CYP2C19 alleles, will enhance clinical understanding of racial differences in drug reactions, contributing to the development of personalised medicine in Asia.

Impacts of CYP2C19 genetic polymorphisms on bioavailability and effect on platelet adhesion of vicagrel, a novel thienopyridine P2Y12 inhibitor.

AIMS: We investigated the impacts of CYP2C19 polymorphisms on pharmacokinetics and pharmacodynamics of vicagrel in healthy Chinese subjects. METHODS: CYP2C19 extensive metabolizers (EMs), intermediate metabolizers (IMs) and poor metabolizers (PMs; 16 subjects/group) participated in a randomized, open-label, 2-period cross-over study. Each study period lasted 7 days, with a loading dose of 24 mg of vicagrel or 300 mg of clopidogrel on day 1, and maintenance doses of 6 mg of vicagrel or 75 mg of clopidogrel daily from day 2 to day 7. The pharmacokinetics and pharmacodynamics were assessed on day 1 and day 7. RESULTS: After a loading dose, the AUC0-t of the active metabolite H4 by vicagrel was slightly lower in IMs and PMs (decreased by 21 and 27%, respectively) compared to EMs. Similar results were found after maintenance doses. In EMs, the AUC0-t of H4 by vicagrel was somewhat higher than clopidogrel after the loading dose, and comparable with clopidogrel (90% confidence interval 0.94, 1.21) after the maintenance doses. However, it was much higher than clopidogrel in PMs, with a 1.28-fold (loading dose) and a 73% (maintenance doses) increases compared to clopidogrel (P < 0.001). Consequently, the inhibition of platelet aggregation by vicagrel was greater than clopidogrel after both loading dose (28.2 vs 12.4% at 4 hours, P < 0.01) and maintenance doses (42.8 vs 24.6% at 4 hours, P < 0.001) in PMs. CONCLUSIONS: CYP2C19 polymorphisms have less impact on vicagrel as compared to clopidogrel. Drug exposure and response to vicagrel in PMs were even higher than to clopidogrel in IMs.

A Prospective Study on the Usefulness of Initial Voriconazole Dose Adjustment Based on CYP2C19 Gene Polymorphism Analysis.

Genetic polymorphism exists for CYP2C19, a dominant metabolic enzyme of voriconazole (VRCZ), and VRCZ pharmacokinetics has been shown to fluctuate according to the CYP2C19 phenotype. Although dosages for different phenotypes have been recommended in various retrospective studies, few reports have adjusted the initial VRCZ dose based on CYP2C19 phenotype determined prior to administration. In this study, we prospectively evaluated the usefulness of CYP2C19 polymorphism analysis in adjusting the initial VRCZ maintenance dose. The study enrolled 19 patients who underwent analysis of CYP2C19 polymorphism prior to VRCZ administration. Subjects were classified into 3 phenotype subgroups: extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM). The initial VRCZ maintenance doses given twice daily were proposed as follows: approximately 8, 6, and 4 mg/kg/day for EM, IM and PM, respectively, according to previous reports. In EM, the initial maintenance dose was 8.0 ± 0.5 mg/kg/day, and trough level was 6.6 ± 2.4 µg/mL. By contrast, the initial maintenance doses in IM and PM were 5.5 ± 0.7 and 4.1 ± 0.3 mg/kg/day, and the initial trough concentrations were 2.9 ± 1.2 and 2.6 ± 0.4 µg/mL, respectively. The attainment rate of target trough concentration of 1-6 µg/mL was 50% in EM, and was 100% in IM and PM. Determining the initial dose of VRCZ only by phenotype based on CYP2C19 gene polymorphism was found to be challenging. However, decreasing the initial maintenance dose in IM and PM may be important for adjusting the initial trough level to target range.

Population pharmacokinetics of voriconazole and CYP2C19 polymorphisms for optimizing dosing regimens in renal transplant recipients.

AIMS: The aims of the present study were to characterize the pharmacokinetics of voriconazole in renal transplant recipients and to identify factors significantly affecting pharmacokinetic parameters. We also aimed to explore the optimal dosing regimens for patients who developed invasive fungal infections. METHODS: A total of 105 patients (342 concentrations) were included prospectively in a population pharmacokinetic analysis. Nonlinear mixed-effects models were developed using Phoenix NLME software. Dosing simulations were performed based on the final model. RESULTS: A one-compartment model with first-order absorption and elimination was used to characterize voriconazole pharmacokinetics. Population estimates of clearance, volume of distribution and oral bioavailability were 2.88 l·h-1 , 169.3 l and 58%, respectively. The allele frequencies of cytochrome P450 gene (CYP) 2C19*2, *3 and *17 variants were 29.2%, 5.2% and 0.5%, respectively. CYP2C19 genotype had a significant effect on the clearance. Voriconazole trough concentrations in poor metabolizers were significantly higher than in intermediate metabolizers and extensive metabolizers alike. The volume of distribution increased with increased body weight. The oral bioavailability was substantially lower within 1 month after transplantation but increased with postoperative time. Dosing simulations indicated that during the early postoperative period, poor metabolizers could be treated with 150 mg intravenously or 250 mg orally twice daily; intermediate metabolizers with 200 mg intravenously or 350 mg orally twice daily; and extensive metabolizers with 300 mg intravenously twice daily. CONCLUSIONS: Using a combination of CYP2C19 genotype and postoperative time to determine the initial voriconazole dosing regimens followed by therapeutic drug monitoring could help to advance individualized treatment in renal transplantation patients with invasive fungal infections.

Body Mass Index and Plasma P-Selectin before Coronary Stenting Predict High Residual Platelet Reactivity at 6 Months on Dual Antiplatelet Therapy.

BACKGROUND: High residual platelet reactivity (HRPR) during dual antiplatelet therapy (DAPT) may impact clinical outcomes following percutaneous coronary interventions (PCI). However, whether any biomarkers assessed before PCI at DAPT loading may predict delayed maintenance HRPR is not clear. OBJECTIVE: The aim of this study was to determine whether conventional clinical or laboratory indices at loading before stenting may predict HRPR at 6 months of maintenance DAPT. METHODS: The study was designed on a single-center prospective cohort, and included 94 pre-PCI patients. All patients underwent elective PCI with drug-eluting stent implantation, and received DAPT with aspirin and clopidogrel. Platelet reactivity was assessed with 5 µmol/L of adenosine diphosphate-induced light transmission aggregometry before PCI, but after 24 h of DAPT loading, and repeated at 6 months. Baseline clinical characteristics, CYP2C19 polymorphism, C-reactive protein, soluble P-selectin, CD40L, interleukin-6, PAI-1 levels, and von Willebrand factor activity were analyzed. RESULTS: The incidence (light transmission aggregometry <50%) of prestent HRPR was 16%. By univariate regression, body mass index (BMI; p = 0.02), total cholesterol (p = 0.01), low-density lipoproteins (p = 0.004), CYP2C19*2 allele carriage (p = 0.006), soluble P-selectin (p = 0.009), and von Willebrand factor (p = 0.04) were linked to future HRPR. However, multivariate regression analysis suggested that only BMI and P-selectin were independent predictors of HRPR. CONCLUSIONS: Platelet reactivity before elective stenting is associated with numerous biomarkers; however, only BMI and soluble P-selectin were independent predictors of future HRPR during maintenance-phase DAPT. This may be important for future tailored antiplatelet strategies in patients with metabolic syndrome and diabetics.

Dual therapy with clopidogrel and aspirin prevents early neurological deterioration in ischemic stroke patients carrying CYP2C19*2 reduced-function alleles.

PURPOSE: To investigate the associations between CYP2C19 genotypes and early neurological deterioration (END), and to carry out a stratified analysis of the effectiveness of clopidogrel alone and dual antiplatelet therapy with clopidogrel and aspirin for prevention of END according to CYP2C19 genotypes in ischemic stroke (IS) patients. METHODS: This was a prospective, observational, two-center study. A total of 375 acute IS patients were enrolled. Platelet aggregation was measured before and after the 7- to 10-day treatment. Clopidogrel resistance (CR) was assessed by adenosine diphosphate-induced platelet aggregation. CYP2C19*2 (rs4244285) and CYP2C19*3 (rs4986893) genotypes were examined using mass spectrometry. The primary outcome was END during the 10 days after admission. RESULTS: Among the 375 patients, 144 patients received clopidogrel alone, 231 patients took clopidogrel plus aspirin, 153 patients (40.8%) had CR, 95 patients (25.3%) experienced END. Patients carrying CYP2C19*2 AG/AA (CYP2C19*2 reduced-function alleles) and CR were associated with a higher risk for END, and dual antiplatelet therapy was associated with a lower risk for END. Stratified analyses revealed that there was no significant difference in the incidence of END between patients not carryingCYP2C19*2 reduced-function alleles who received clopidogrel plus aspirin and those who received clopidogrel alone. However, dual antiplatelet therapy was more effective at reducing END and inhibiting platelet aggregation than clopidogrel alone for carriers of at least one CYP2C19*2 reduced-function allele. CONCLUSIONS: The frequency of END was very high after acute IS in the Chinese population. Dual therapy with clopidogrel and aspirin may be adequate for patients carrying CYP2C19*2 reduced-function alleles. Genetic testing may be useful to guide personalized and precise antiplatelet therapy. CLINICAL TRIAL REGISTRATION INFORMATION: The study described here is registered at http://www.chictr.org / (unique Identifier: ChiCTR-OCH-14004724).

[High On-Treatment Platelet Reactivity Determinants on Dual Antiplatelet Therapy in Patients With Ischemic Heart Disease Before Elective Percutaneous Coronary Intervention].

OBJECTIVE: to determine impact of different laboratory and genetic factors on high on-treatment platelet reactivity (HOPR) during dual antiplatelet therapy (DAPT). METHODS: We included in this study 94 patients with stable ischemic heart disease (mean age 59±9.67 years). All patients underwent elective PCI with implantation of drug eluting stents at the background of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. Platelet reactivity was assessed using light transmission aggregometry with 5 µmol/L ADP (LTA 5ADP) and VerifyNow assay before PCI. All patients underwent genotyping to detect CYP2C19 polymorphism. In 74 patients at baseline examination we determined levels of high-sensitivity C-reactive protein (hsCPR), soluble platelet-selectin (sP-selectin), soluble CD40­ligand (sCD40L), interleukin-6 (IL-6), plasminogen activator inhibitor (PAI-1) and activity of von Willebrand factor. RESULTS: Incidence of HOPR according to LTA-5ADP was 16 % and VerifyNow - 24.5 %. Univariate regression analysis showed that the following factors were significantly associated with HPR determined by LTA-5ADP: body mass index (BMI) (p=0.02), levels of total cholesterol (CH) (p=0.01), low density lipoprotein CH (p=0.004), and sP-selectin (p=0.009), activity of von Willebrand factor (p=0.04). Carriage of CYP2C19*2 allele was also associated with HOPR (p=0.006). According to multivariate regression analysis body mass index and level of sP-selectin were independent predictors of HOPR during DAPT. CONCLUSIONS: HOPR determined by LTA was significantly associated with high BMI, levels of total and LDL CH, carriage of CYP2C19*2 allele, levels of hsCRP and sP-selectin. Independent factors significantly related to HORP were BMI and sP-selectin level.

Effects of CYP2C19 Variants on Fluoxetine Metabolism in vitro.

AIMS: CYP2C19 is an important member of the cytochrome P450 enzyme superfamily. We recently identified 31 CYP2C19 alleles in the Han Chinese population. The aim of this study was to assess the catalytic activities of these allelic isoforms and their effects on the metabolism of fluoxetine in vitro. METHODS: The wild-type and 30 CYP2C19 variants were expressed in insect cells and each variant was characterized using fluoxetine as the substrate. Reactions were performed at 37°C with 20-1,000 µmol/L substrate for 30 min. By using ultra-high performance liquid chromatography-mass spectrometry to detect the products, the kinetic parameters Km, Vmax, and intrinsic clearance (Vmax/Km) of norfluoxetine were determined. RESULTS: Among the CYP2C19 variants tested, T130M showed similar intrinsic clearance (Vmax/Km) values with CYP2C19*1, while the intrinsic clearance values of other variants were significantly decreased (from 9.56 to 77.77%). In addition, CYP2C19*3 and *35FS could not be detected because they have no detectable enzyme activity. CONCLUSION: In China, the assessment of CYP2C19 variants in vitro offers valuable information relevant to the personalized medicine for CYP2C19-metabolized drug.

Effect of CYP2C19 polymorphism on response to bortezomib-based therapy in multiple myeloma patients.

BACKGROUND: Bortezomib, a commonly used anti-myeloma drug, is metabolized by liver microsomal enzymes which may be polymorphic and responsible for lack of response in 30% patients. Hence, the association of CYP2C19 polymorphism with treatment response was explored in this study. METHODS: Treatment naive multiple myeloma (MM) patients, eligible for bortezomib-based induction treatment, were recruited as per the inclusion - exclusion criteria. The genotyping of CYP2C19 was done using polymerase chain reaction-restriction fragment length polymorphism for *2, *3 and *17 alleles. The incidence and severity of peripheral neuropathy were noted at follow-up visits and graded as per CTCAE criteria ver 5.0. RESULTS: Total 220 patients were recruited from August 2016 till May 2021; with a mean age of 55.6 (9.5) years and 65.9% males. Bortezomib+cyclophosphamide+dexamethasone (41.8%) and bortezomib+lenalidomide+dexamethasone (38.2%) were the most prescribed regimens. The CYP2C19 was polymorphic in 38.6%, 2.3% and 23.7% patients for *2, *3 and *17 allele respectively. There were 195 treatment responders and 25 non-responders, and CYP2C19*2 allele was different between responders and non-responders (p = 0.02). All extensive metabolisers (n = 54) were noted to be treatment responders. Peripheral neuropathy was reported by 23.2% patients. The frequency of peripheral neuropathy was somewhat lower in patients having either *2/*2 or *3/*3 allele pattern for CYP2C19 (p = 0.44). CONCLUSIONS: Polymorphism in CYP2C19 enzyme is likely to have an impact on bortezomib treatment response and peripheral neuropathy. The study suggests the role of pharmacogenetics in personalised treatment of MM.

The effect of CYP2C19 polymorphism on the safety, tolerability, and pharmacokinetics of tivantinib (ARQ 197): results from a phase I trial in advanced solid tumors.

BACKGROUND: Tivantinib (formerly ARQ 197) is a selective inhibitor of c-Met mainly metabolized by CYP2C19. CYP2C19 is known for genetic polymorphisms, and ~20% of Asians are poor metabolizers (PMs), while others are extensive metabolizers (EMs). In this study, we examined the safety, pharmacokinetics (PK), and preliminary efficacy of tivantinib as a single agent to determine recommended phase II doses (RPIIDs). PATIENTS AND METHODS: Forty-seven patients (EMs, 33; PMs, 14) with solid tumors were orally treated with tivantinib, from 70 to 360 mg bid in a 3 + 3 dose-escalation scheme. EMs and PMs were separately enrolled at the doses >120 mg bid. RESULTS: Tivantinib was well tolerated up to 360 mg bid for EMs and 240 mg bid for PMs. Neutropenia, leukopenia, anemia, fatigue, and anorexia were the frequent adverse events related to tivantinib and were commonly observed in both EMs and PMs. PMs had 1.9-fold higher AUC(0-12) compared with EMs at 240 mg bid. Regardless of CYP2C19 phenotype, Gr.4 neutropenia occurred in patients with relatively high exposure to tivantinib. A confirmed partial response was achieved in two non-small-cell lung cancer (NSCLC) patients. CONCLUSION: Two different settings of RPIIDs, 360 mg bid for EMs and 240 mg bid for PMs, were determined.

Elevations in Norclobazam Concentrations and Altered Mental Status in CYP2C19 Poor Metabolizer Phenotype: A Case Report.

Clobazam is a 1,5-benzodiazepine frequently used as an adjunctive agent for refractory seizures and status epilepticus. Clobazam undergoes metabolism to an active metabolite norclobazam which is subsequently hydroxylated by CYP2C19, a cytochrome with several pharmacogenetic variants. Patients with poor metabolizer phenotypes may have elevated norclobazam levels and subsequent adverse effects. We present a case of an Asian American male receiving clobazam at a standard therapeutic dose for seizure disorder who became comatose secondary to significantly elevated norclobazam concentrations. Genetic testing revealed the patient was a poor CYP2C19 metabolizer, accounting for the impaired clearance. Clinicians should be aware of the patient populations at risk for these genetic polymorphisms and adjust initial doses based on package labeling or consider therapeutic drug monitoring to avoid adverse effects.

Validating the Prognostic Utility of the ABCD-GENE Score in Asian Patients with Acute Coronary Syndrome Patients on Clopidogrel.

Background: The ABCD-GENE score, which links cytochrome P450 2C19 (CYP2C19) phenotype and high platelet reactivity (HPR) to the risk of major adverse cardiovascular events (MACE) in clopidogrel users, has been validated in white and Japanese populations. The prognostic implications of the score in other Asian cohorts, however, have been largely unchartered. The aim of this study was to validate the prognostic utility of the ABCD-GENE score in a heterogeneous Asian acute coronary syndrome (ACS) cohort. Methods and Results: In this single-centre, retrospective cohort evaluation of 423 ACS patients, the objectives were to characterise the best cut-off score for MACE prognostication by comparing the adjusted 1-year risk of MACE between groups above and below the candidate cut-off scores using Cox regression; and for on-clopidogrel HPR prediction using receiver operating characteristic (ROC) analysis and Youden's index. In the adjusted Cox model, an ABCD-GENE score cut-off at 10 points significantly predicts the 1-year risk of MACE (adjusted HR 3.771; 95% CI [1.041-13.661]). Female sex, baseline LDL, history of ACS and angiotensin receptor blocker use were additional independent predictors of MACE. On ROC analysis the ideal cut-off for HPR prediction was 7 points. However, that did not independently predict the 1-year risk of MACE (adjusted HR 1.595; 95% CI [0.425-5.989]). Conclusion: The original ABCD-GENE score 10-point cut-off moderately predicts MACE in a heterogeneous, Asian ACS population at 1 year. Additional predictors of MACE were also identified in the present cohort, and these findings should be prospectively validated in larger ACS cohorts.

Utility of the ACD-GENE-CLI Score in Asian Patients with Critical Limb Ischemia Undergoing Endovascular Interventions.

AIMS: Critical limb ischemia (CLI) is an emerging public health threat and lacks a reliable score for predicting the outcomes. The Age, Body Mass Index, Chronic Kidney Disease, Diabetes, and Genotyping (ABCD-GENE) risk score helps identify patients with coronary artery disease who have cytochrome P450 2C19 (CYP2C19) polymorphism-related drug resistance and are at risk for cardiovascular adverse events. However, its application to CLI remains unknown. In this study, we aim to validate a modified ACD-GENE-CLI score to improve the prediction of major adverse limb events (MALEs) in patients with CLI receiving clopidogrel. METHODS: Patients with CLI receiving clopidogrel post-endovascular intervention were enrolled prospectively in two medical centers. Amputation and revascularization as MALEs were regarded as the outcomes. RESULTS: A total of 473 patients were recruited, with a mean follow-up duration of 25 months. Except for obesity, old age, diabetes, chronic kidney disease (CKD), and CYP2C19 polymorphisms were significantly associated with MALEs. Using bootstrap regression analysis, we established a modified risk score (ACD-GENE-CLI) that included old age (≥ 65 years), diabetes, CKD, and CYP2C19 polymorphisms. At a cutoff value of 8, the ACD-GENE-CLI score was superior to the CYP2C19 deficiency only, and the conventional ABCD-GENE score in predicting MALEs (area under the curve: 0.69 vs. 0.59 vs. 0.67, p=0.01). The diagnostic ability of the ACD-GENE-CLI score was consistent in the external validation. Also, Kaplan-Meier curves showed that in CYP2C19 deficiency, the ABCD-GENE and ACD-GENE-CLI scores could all differentiate patients with CLI who are free from MALEs. CONCLUSIONS: The modified ACD-GENE-CLI score could differentiate patients with CLI receiving clopidogrel who are at risk of MALEs. Further studies are required to generalize the utility of the score.

Analysis of Combined Effect of CYP2C19 Genetic Polymorphism and Proton Pump Inhibitors Coadministration on Trough Concentration of Voriconazole.

PURPOSE: To analyze the combined effect of CYP2C19 genetic polymorphism and PPIs coadministration on voriconazole trough concentration (VCZ-Ctrough) in Chinese patients with hematological disorders. PATIENTS AND METHODS: A prospective observational study involved 250 plasma samples from 114 adult patients receiving voriconazole with or without PPIs were analyzed. Demographics and clinical characteristics were obtained from patient's records. A validated LC-MS/MS was used to quantify the plasma VCZ-Ctrough. Genotyping for CYP2C19*2 and CYP2C19*3 variant alleles was performed by PCR-RFLP followed by DNA sequencing. The combined total score (from 2 to 5) was calculated for each patient. The higher the score, the lesser the metabolism of the patient. FINDINGS: Fifty percent of patients administered with voriconazole were coadministered with PPIs, predominantly omeprazole or esomeprazole. Patients exhibiting CYP2C19 poor metabolizer phenotype showed a significantly higher median VCZ-Ctrough, (4.31µg/mL [IQR, 1.64µg/mL-7.36µg/mL]) than patients with normal metabolizer (1.38µg/mL, [IQR, 0.79µg/mL-2.14µg/mL], p < 0.0001). Similarly, patients co-administration with PPIs had higher median VCZ-Ctrough (2.86µg/mL [IQR 1.33µg/mL-4.66µg/mL]), than PPIs non-users (1.71µg/mL, [IQR, 0.86µg/mL-3.48µg/mL], p = 0.001). However, we noted that the median VCZ-Ctrough for each factor was ranging within the normal recommended therapeutic range in the Chinese population (0.5µg/mL-5µg/mL). But when the two factors were combined, the median VCZ-Ctrough was steadily increasing as the metabolic capacity (reflected by combined total score) was increasing. Importantly, the median VCZ-Ctrough in PM/PPIs user (total score 5) was significantly elevated to supra-therapeutic levels compared to NM/PPI non-user group (total score 2) (5.83µg/mL [IQR, 2.19µg/mL-9.51µg/mL] versus 1.13µg/mL [IQR, 0.67µg/mL-1.82µg/mL]), respectively, P < 0.0001. Furthermore, we observed that the elevation of median VCZ-Ctrough to supra-therapeutic levels was largely contributed by omeprazole or esomeprazole compared to lansoprazole or pantoprazole. CONCLUSION: Coadministration with PPIs significantly increased voriconazole trough concentrations and there was an additive effect in CYP2C19 PMs, who were most likely to have supra-therapeutic levels.

Variants *1, *2, *3 and *17 of CYP2C19 Cytochrome among Helicobacter Pylori Carriers from Manaus, Amazonas State, Brazil.

OBJECTIVE: The objective of the present study was to estimate the frequency of CYP2C19 cytochrome variants *1, *2, *3 and *17 among Helicobacter pylori carriers from Manaus, Amazonas state, who were treated at Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD). METHODS: From the 78 recruited individuals who underwent upper gastrointestinal endoscopy with biopsy and histopathological test, 50 tested positive for H. pylori. Peripheral blood was collected from this group and CYP2C19 *2, *3 and *17 alleles were genotyped using qPCR. RESULTS: Of the 50 H. pylori + individuals, 22 were male and 28 were female. Their age varied from 18 to 67 years old, with the mean age being 40.24. Racial groups were classified by self-declaration, based on the official Instituto Brasileiro de Geografia e Estatística (IBGE) categories: 16% (8) were white, 78% (39) were brown, 4% (2) were black, and 2% (1) were indigenous. H. pylori infection was classified using the system of crosses, with 30% (15) of infections being classified as mild (+), 30% (15) as moderate (++), and 40% (20) as severe (+++). The CYP2C19 genotype results showed an allelic frequency of 11% for *2 (20% of the subjects), 6% for *3 (10% of the subjects) and 17% for *17 (30% of the subjects). Based on the phenotypic profiles, the individuals were classified as poor metabolizers (PM, 10%), intermediate metabolizers (IM, 2%), extensive metabolizers (EM, 58%) and ultra-rapid metabolizers (UM, 20%). CONCLUSIONS: Even though the percentage of allele *3 was higher than expected, the percentage of allele *17, a possible contributor to H. pylori eradication failure, was also significant. The population that self-declared as brown showed a unique genotypic pattern, unlike any other population described in previous studies. Our results show that small populations may have genetic particularities that are relevant to therapeutic outcomes.
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Impacts of CYP2C19 Polymorphism and Clopidogrel Dosing on in-Stent Restenosis: A Retrospective Cohort Study in Chinese Patients.

OBJECTIVE: This retrospective cohort study is to analyze the impacts of CYP2C19 polymorphism and clopidogrel dosing on in-stent restenosis (ISR) after coronary stenting. METHODS: Totally, 111 patients were included, who underwent percutaneous coronary intervention (PCI) with drug-eluting stent. Patients received clopidogrel treatment after the intervention on the background treatment with aspirin, based on the genotypes: 75 mg clopidogrel once each day for subjects without CYP2C19 loss-of-function (LOF) alleles (n=51; EM), 75 mg clopidogrel once each day (n=27; IM75) or twice each day (n=33; IM150) for subjects with one CYP2C19 LOF allele. ISR at 3-18 months after coronary stenting was assessed. RESULTS: ISR rate was significantly higher in the IM75 group (40.7%) than the EM group (11.8%). ISR rate in the IM150 group was lower than the IM75 group (6.1% vs 40.7%), and comparable to that in the EM group. Multivariate logistic regression showed that both CYP2C19 genotype and clopidogrel dosing were associated with the risk of ISR after adjusting the relevant confounding factors. ISR risk was higher in the IM patients than the EM patients. Patients with clopidogrel dose of 75 mg once each day had significantly higher risk of ISR than those with the dose of 75 mg twice each day. CONCLUSION: Increased dose of clopidogrel may reduce the risk of ISR after PCI in CYP2C19 LOF allele(s) carriers. The presence of CYP2C19 LOF allele(s) increases the risk of ISR after stenting, which could be counteracted by the increased dose of clopidogrel.