Prediction of the Impact of CYP2C19 Polymorphism on Drug-Drug Interaction between Voriconazole and Tacrolimus Using Physiologically-Based Pharmacokinetic Modelling

Abstract Voriconazole increases tacrolimus blood concentration significantly when coadministrated. The recommendation of reducing tacrolimus to 1/3 in voriconazole package insert seems not to be satisfactory in clinical practice. In vitro studies demonstrated that the magnitude of inhibition depends on the concentration of voriconazole, while voriconazole exposure is determined by the genotype status of CYP2C19. CYP2C19 gene polymorphism challenges the management of drug-drug interactions(DDIs) between voriconazole and tacrolimus. This work aimed to predict the impact of CYP2C19 polymorphism on the DDIs by using physiologically based pharmacokinetics (PBPK) models. The precision of the developed voriconazole and tacrolimus models was reasonable by evaluating the pharmacokinetic parameters fold error, such as AUC0-24, Cmax and tmax. Voriconazole increased tacrolimus concentration immediately in all population. The simulated duration of DDIs disappearance after voriconazole withdrawal were 146h, 90h and 66h in poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers(EMs), respectively. The developed and optimized PBPK models in this study can be applied to assit the dose adjustment for tacrolimus with and without voriconazole.

Efficacy analysis of anti-platelet in the treatment of high-risk non-disabling ischemic cerebrovascular events guided by point-of-care testing of CYP2C19 gene / 中华神经科杂志

Objective:To explore the efficacy and safety of different anti-platelet regimens in the treatment of high-risk non-disabling ischemic cerebrovascular events (HR-NICE) guided by point-of-care testing of CYP2C19 gene. Methods:A single-centre, prospective, randomised, open-label, and blinded endpoint design was uesd in the study. From July 2020 to January 2022, HR-NICE patients were enrolled in the Stroke Green Channel and Department of Neurology of Xuzhou Central Hospital, and all patients were scraped the buccal mucosa for screening for CYP2C19 loss-of-function allele carriers by point-of-care testing . Patients with intermediate metabolism were defined as those who carried 1 loss-of-function allele and patients with poor metabolism were those who carried 2 loss-of-function alleles. This study reduced the test turnaround time to 1 hour by using a fully automated medical polymerase chain reaction analyzer for a point-of-care test of CYP2C19 genotype. CYP2C19 loss-of-function allele carriers were divided according to the random number table method into the conventional treatment group (clopidogrel 75 mg, once a day), the ticagrelor group (ticagrelor 90 mg, twice a day) and the intensive dose group (clopidogrel 150 mg, once a day) separately combined with aspirin (100 mg, once a day) dual antiplatelet for 21 days. Baseline information, Acute Stroke Org 10172 Treatment Trial staging, 90-day modified Rankin Scale score, occurrence of adverse events and severe adverse events were collected for all the 3 groups. The primary efficacy outcome was new stroke within 90 days, and the primary safety outcome was severe or moderate bleeding within 90 days. Results:A total of 716 patients were included: 240 in the conventional treatment group, 240 in the ticagrelor group and 236 in the intensive dose group. There was no statistically significant difference between the 3 groups at baseline (all P>0.05). There were 26 cases (10.8%) with new stroke events in the conventional treatment group, 11 cases (4.6%) in the ticagrelor group and 4 cases (1.7%) in the intensive dose group, with statistically significant differences among the 3 groups (χ 2=19.28, P<0.05), and the differences between the conventional treatment group and the ticagrelor group (χ 2=6.59, P=0.010) and between the conventional treatment group and the intensive dose group (χ 2=16.83, P<0.001) were statistically significant, whereas the difference between the ticagrelor group and the intensive dose group was not statistically significant ( P>0.05). In the 3 groups, there was 1 case (0.4%) of severe bleeding in the conventional treatment group, 6 cases (2.5%) in the ticagrelor group and none in the intensive dose group, which showed statistically significant differences (χ 2=7.23, P<0.05), and there was statistically significant difference between the ticagrelor group and the intensive dose group ( P=0.030). Among the patients with intermediate CYP2C19 metabolism, there were 13 cases (13/158, 8.2%) with 90-day recurrent stroke in the conventional treatment group, 4 cases (4/153, 2.6%) in the ticagrelor group, and 0 case (0/159) in the intensive dose group, with statistically significant difference (χ 2=16.04, P<0.001), and the differences between the intensive dose group and the conventional treatment group were statistically significant (χ 2=13.64, P<0.001), whereas there was no statistically significant difference between the intensive dose group and the ticagrelor group ( P>0.05). In the patients with 90-day recurrent stroke in the intensive dose group, there was 0 case (0/159) with intermediate metabolism and 4 cases (4/77,5.2%) with poor metabolism, with statistically significant differences ( P=0.011), whereas there were no statistically significant differences in the conventional treatment group and the ticagrelor group ( P>0.05). Conclusions:Screening carriers of CYP2C19 loss-of-function alleles by point-of-care testing can quickly and precisely guide the treatment of patients with non-cardiogenic HR-NICE. An intensive clopidogrel dose of 150 mg, once a day combined with aspirin was effective in reducing stroke recurrence with less occurrence of any bleeding and adverse events, and patients with intermediate CYP2C19 metabolism may be the best population to benefit.

The effect of CYP2C19 genetic polymorphism on proton pump inhibitors and the efficacy of Hp eradication in children / 国际儿科学杂志

The polymorphism of CYP2C19 gene constitutes the basis for the difference in enzyme activity and affects the metabolism of many drugs including proton pump inhibitors.The distribution of CYP2C19 gene varies by region and race.The study on the relationship between CYP2C19 genotype and proton pump inhibitors is of great significance for the individualized treatment of Helicobacter pylori (Hp) in children.This paper reviews the effects of CYP2C19 gene polymorphism on proton pump inhibitors and the efficacy of Hp eradication in children.

Antiplatelet and myocardial protective effect of Shexiang Tongxin Dropping Pill in patients undergoing percutaneous coronary intervention: A randomized controlled trial / 中西医结合学报

BACKGROUND@#High on-clopidogrel platelet reactivity could be partially explained by loss-of-function alleles of CYP2C19, the enzyme that converts clopidogrel into its active form. Shexiang Tongxin Dropping Pill (STDP) is a traditional Chinese medicine to treat angina pectoris. STDP has been shown to improve blood flow in patients with slow coronary flow and attenuate atherosclerosis in apolipoprotein E-deficient mice. However, whether STDP can affect platelet function remains unknown.@*OBJECTIVE@#The purpose of this study is to examine the potential effects of STDP on platelet function in patients undergoing percutaneous coronary intervention (PCI) for unstable angina. The interaction between the effects of STDP with polymorphisms of CYP2C19 was also investigated.@*DESIGN, PARTICIPANTS AND INTERVENTION@#This was a single-center, randomized controlled trial in patients undergoing elective PCI for unstable angina. Eligible subjects were randomized to receive STDP (210 mg per day) plus dual antiplatelet therapy (DAPT) with clopidogrel and aspirin or DAPT alone.@*MAIN OUTCOME MEASURES@#The primary outcome was platelet function, reflected by adenosine diphosphate (ADP)-induced platelet aggregation and platelet microparticles (PMPs). The secondary outcomes were major adverse cardiovascular events (MACEs) including recurrent ischemia or myocardial infarction, repeat PCI and cardiac death; blood biomarkers for myocardial injury including creatine kinase-MB isoenzyme (CK-MB) and high-sensitive troponin I (hsTnI); and biomarkers for inflammation including intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and galectin-3.@*RESULTS@#A total of 118 subjects (mean age: [66.8 ± 8.9] years; male: 59.8%) were included into analysis: 58 in the control group and 60 in the STDP group. CYP2C19 genotype distribution was comparable between the 2 groups. In comparison to the control group, the STDP group had significantly lower CK-MB (P < 0.05) but similar hsTnI (P > 0.05) at 24 h after PCI, lower ICAM-1, VCAM-1, MCP-1 and galectin-3 at 3 months (all P < 0.05) but not at 7 days after PCI (P > 0.05). At 3 months, the STDP group had lower PMP number ([42.9 ± 37.3] vs. [67.8 ± 53.1] counts/μL in the control group, P = 0.05). Subgroup analysis showed that STDP increased percentage inhibition of ADP-induced platelet aggregation only in slow metabolizers (66.0% ± 20.8% in STDP group vs. 36.0% ± 28.1% in the control group, P < 0.05), but not in intermediate or fast metabolizers. The rate of MACEs during the 3-month follow-up did not differ between the two groups.@*CONCLUSION@#STDP produced antiplatelet, anti-inflammatory and cardioprotective effects. Subgroup analysis indicated that STDP inhibited residual platelet reactivity in slow metabolizers only.@*TRIAL REGISTRATION@#This study was registered on www.chictr.org.cn: ChiCTR-IPR-16009785.

The analysis on the correlation between CYP2C19 gene polymorphism and clopidogrel resistance in patients with acute coronary syndrome / 中国医师进修杂志

Objective:To analyze the relationship between CYP2C19 polymorphism and clopidogrel resistance (CR) in patients with acute coronary syndrome (ACS).Methods:One hundred and twenty-seven ACS patients treated with percutaneous coronary intervention (PCI) from June 2019 to June 2020 were enrolled, including 29 patients with CR(CR group) and 98 patients with none clopidogrel resistance (NCR, NCR group). The clinical data, coronary angiography results were compared between the two groups, the relationship of CYP2C19*2 and CYP2C19*3 polymorphisms and CR were analyzed.Results:The general data and coronary angiography between two groups had no significant differences ( P>0.05). There were differences in the distribution of isogenic genes and genotypes of CYP2C19 (rs4244285) and CYP2C19 (rs4986893) between the two groups ( P<0.05). Polymorphism of CYP2C19*2 and CYP2C19*3 was an important risk factor for CR ( OR = 14.688, 95% CI 3.652-59.063, P<0.01; OR = 7.228, 95% CI 2.412-21.663, P<0.01). Conclusions:CR is closely associated with CYP2C19*2 and CYP2C19*3 in ACS patients.

Qualidade de vida, sintomas de depressão e adesão ao tratamento em pacientes com trantorno depressivo maior / Quality of life, depression symptoms and adherence to treatment in patients with major depressive disorder / Calidad de vida, síntomas depresión y adhesión al tratamiento en pacientes con trastorno depresivo mayor

Introdução:Pacientes com depressão maior geralmente respondem ao tratamento com medicamentos antidepressivos, no entanto em 10% a 30% dos casos há apenas uma resposta parcial ou nenhuma resposta, entre os fatores que podem influenciar encontra-se o perfil das enzimas hepáticas metabolizadoras dos antidepressivos, tal como a CYP2C19.Objetivo:Caracterizar os indivíduos quanto ao perfil genético dospolimorfismos CYP2C19*2 ou CYP2C19*17 em pacientes com transtorno depressivo maior (TDM) tratados com citalopram ou escitalopram e compará-los em relação a adesão ao tratamento, sintomas de depressão e qualidade de vida.Metodologia:Trata-se de um estudo transversal realizado com 29 pacientes com TDM. Amostras de sangue foram coletadas para genotipagem de CYP2C19 por discriminação alélica TaqMan®. Após caracterização do perfil genético, os indivíduos foram comparados quanto aos dados demográfico e socioeconômico, adesão ao tratamento (TestedeMorisky-Green),sintomas de depressão (escala de Hamilton) e qualidade de vida (WHOQoL-BREF).Resultados:Quatro pacientes (13.8%) apresentaram polimorfismo para CYP2C19*2 e 10 pacientes (34.4%) para CYP2C19*17, com maior prevalência de CYP2C19*17 (p>0.05). Nenhuma associação significativa de características socioeconômicas, demográficas e clínicas entre os genótipos do CYP2C19.No TestedeMorisky-Green, aadesão moderada ao tratamento foi predominante nos pacientes CYP2C19*2 e CYP2C19*17 (p>0.05). Não foi observada associação entre sintomas de depressão e polimorfismos genéticos (p>0.05). Uma associação significativa entre o genótipo polimórfico CC do CYP2C19*17 com a satisfação com a saúde, enquanto o genótipo CT foi associado ao estado "nem satisfeito/nem insatisfeito" (p<0.05). A maioria dos indivíduos CYP2C19*2 e CYP2C19*17 relatou "necessidade de melhorar" em relação aos domínios de qualidade de vida físico, psicológico, social e ambiental (p>0.05).Conclusões:Os pacientes apresentaram maior prevalência do polimorfismo CYP2C19*17, com moderada adesão ao tratamento. Alguns pacientes, mesmo sob efeito da medicação, apresentaram sintomas de depressão moderado a intenso e relataram uma indefinição na satisfação da sua qualidade de vida (AU).

Introduction:Patients with major depression usually respond to treatment with antidepressant drugs, however in 10% to 30% of cases there is only a partial response or no response, among the factors that can influence is the profile of liver enzymes metabolizing antidepressants, such as CYP2C19.Objective:To characterize the individuals regarding the genetic profile ofCYP2C19*2or CYP2C19*17 polymorphisms in patients with major depressive disorder (MDD) treated with citalopram or escitalopram, and to compare themaccording to treatment adherence, symptoms of depression and quality of life.Methodology:This is cross-sectionalstudy carried out with 29 patients with MDD. Blood samples were collected for CYP2C19 genotyping by TaqMan® allelic discrimination. After characterization of the genetic profile, the individuals were compared regarding the demographic and socioeconomic data, treatment adherence (Morisky-GreenTest), symptoms of depression (Hamilton scale) and quality of life (WHOQoL-BREF).Results:Four patients showed (13.8%) CYP219*2 and 10 patients (34.4%) CYP219*17 polymorphisms.,withhigher prevalence of CYP219*17 (p>0.05). No association between socioeconomic, demographic, and clinical features with CYP2C19 genotypes was observed. In Morisky-GreenTest, moderate adherence to treatment was predominant for CYP2C19*2 and CYP219*17 patients (p>0.05). No statistically significant association was observed between symptoms of depression and genetic polymorphisms (p>0.05). A significant association between polymorphic CC genotype of CYP219*17 with health satisfaction, while the CT genotype was associated with "neither satisfied/nor dissatisfied" status (p<0.05). Most of the CYP2C19*2 and CYP2C19*17 subjects reported "need to improve" or "regular" regarding physical, psychological, social, and environmental domainsof quality of life(p>0.05).Conclusions:The patients showed a higher prevalence of CYP219*17 polymorphism, with moderate treatment adherence. Some subjects, even under the effect of the medication, presented moderate to intense symptoms of depression, and reported a lack of definition in the satisfaction of their quality of life (AU).

Introducción:Los pacientes con depresión mayor responder al tratamiento con antidepresivos, en 10% al 30% de los casos existe una respuesta parcial o nula, entre los factores que pueden influir se encuentra el perfil de enzimas hepáticas metabolizadoras de antidepresivos, como CYP2C19.Objetivo: Caracterizar a los individuos en cuanto al perfil genético depolimorfismos CYP2C19 *2 o CYP2C19 * 17 en pacientes con trastorno depresivo mayor (TDM) tratados con citalopram o escitalopram y compararlos en relaciónpara la adherencia al tratamiento, síntomas de depresión y la calidad de vida.Metodología: Estudio transversalcon 29 pacientes con TDM. Se recogieron muestras de sangre para la determinación del genotipo CYP2C19 mediante discriminación alélica TaqMan®, los individuos fueron comparados en cuanto a los datosdemográficosy socioeconómicos, adherencia (Prueba de Morisky-Green), síntomas de depresión (escala de Hamilton) y calidad de vida (WHOQoL-BREF).Resultados: Cuatro pacientes (13,8%) con polimorfismo CYP2C19*2 y 10 (34,4%) con CYP2C19 * 17,(p> 0,05). No existe una asociación significativa de las características socioeconómicas, demográficas y clínicas con los genotipos CYP2C19. La adherencia moderada al tratamiento fue predominante en los pacientes con CYP2C19*2 y CYP2C19*17 (p> 0,05). No hubo asociación entre síntomas de depresión y polimorfismos genéticos (p> 0.05). Una asociación significativa entre el genotipo polimórfico CYP2C19 * 17 CC con la satisfacción con la salud, mientras que el genotipo CT se asoció con el estado "ni satisfecho / no insatisfecho" (p <0.05). La mayoría de CYP2C19 * 2 y CYP2C19 * 17 individuos informaron "necesidad de mejorar" en relación con los dominios físico, psicológico, social y ambientalde calidad de vida(p> 0,05).Conclusiones: Los pacients mostraron una mayor prevalencia del CYP2C19 * 17, con adherencia moderada al tratamiento, síntomas de depresión moderada a intensay informaron una falta de definición en la satisfacción de su calidad de vida (AU).

Influence of CYP2C19 genetic polymorphism on the Helicobacter pylori eradication efficacy in children in Chongqing / 中华实用儿科临床杂志

Objective:To investigate the distribution of CYP2C19 genotypes in Helicobacter pylori (Hp) infected children in Chongqing and the correlation of genotypes with gender, age and efficacy, and to provide a reasonable plan for Hp eradication in children in Chongqing. Methods:A prospective clinical cohort study was carried out on 156 children who were suspected of Hp infection and underwent gastroscopy in Children′s Hospital of Chongqing Medical University from March to July 2020. 13C-urea breath test ( 13C-UBT), rapid urease test (RUT) and histological examination were made for all the children included.Meanwhile, for Hp-positive children, the CYP2C19 genotypes were detected by using the polymerase chain reaction(PCR)-sequence-specific primer method, and their sensitivity to Clarithromycin and Amoxicillin was assessed.According to the genetic testing results, the CYP2C19 genotypes were divided into homozygous extensive metabolizer (HomEM), heterozygous extensive metabolizer (HetEM) and poor metabolizer (PM). The eradication outcomes of proton pump inhibitor combined with Amoxicillin and Clarithromycin (PAC) in different genotypes were observed.The measurement data that did not conform to the normal distribution were expressed with the median ( M), and the enumeration data were represented by the rate or the constituent ratio.The Chi- square test was used for comparison between groups, and P<0.05 indicated statistically significant difference. Results:(1)A total of 102 children were Hp positive.Positive rates of 13C-UBT, RUT and histologic results were 97.1% (99/102), 99.0% (101/102), and 90.2% (92/102), respectively.(2)Among the 102 Hp-infected children HomEM accounted for 45.1% (46/102), HetEM for 41.2% (42/102), and PM for 13.7% (14/102). (3)There were 50 males and 52 females in 102 Hp-infected children.The age range was 3 years to 17 years and 9 months (median: 9 years and 7 months). There was no significant difference in the distribution of CYP2C19 genotypes between females and males and among children of different ages (all P>0.05). (4)In 87 cases treated with PAC regimen, 36 cases failed to eradicated Hp in the initial treatment, including 18 cases of HomEM, 15 cases of HetEM, and 3 cases of PM.Hp was eradicated successfully in 51 cases, including 21 cases of HomEM, 21 cases of HetEM and 9 cases of PM.There was no statistically significant difference in the Hp eradication efficacy among children with different CYP2C19 genotypes treated by the PAC regimen ( P>0.05). (5) Among the 87 children, 45 children were sensitive to Clarithromycin, and 37 of them achieved successful Hp eradication.About 42 children were resistant to Clarithromycin, and Hp eradication was fulfilled in 14 of them.There was a statistically significant difference in the Hp eradication efficacy among Clarithromycin-resistant children treated by PAC regimen ( P<0.05). Conclusions:The CYP2C19 genotypes have no correlation with gender, age and Hp eradication efficacy of PAC in children with Hp infection in Chongqing.

Effect of antiplatelet strategy on prognosis of in patients with diabetes mellitus and acute coronary syndrome with different CYP2C19 genotype / 国际生物医学工程杂志

Objective:To investigate the effect of different P2Y12 inhibitors on the long-term prognosis of patients with diabetes mellitus (DM) and acute coronary syndrome (ACS), with or without the CYP2C19 loss-of-function (LOF) gene. Method:266 consecutive ACS patients undergoing percutaneous coronary intervention (PCI) were enrolled. According to the CYP2C19 LOF genotype, the patients were divided into rapid metabolizing-type (without the CYP2C19 LOF gene) and moderate-slow metabolizing type (with the CYP2C19 LOF gene). Each type was divided into the A group (with diabetes) and the B group (without diabetes). Each group was divided into the ticagrelor subgroup and the clopidogrel subgroup according to the type of P2Y12 platelet inhibitor. The MACE events were recorded for each subgroup over 3 years, and the prognostic impact of the CYP2C19 LOF genotype and the type of P2Y12 used were analyzed. Results:There were no significant differences in MACE, revascularization, stroke, heart failure rehospitalization, major bleeding, or all-cause mortality among subgroups of patients with rapid metabolizing type at 3 years after PCI (all P>0.05). In patients with moderate-slow metabolizing-type, the use of tegretol significantly reduced the probability of MACE events and cardiac revascularization (all P<0.01) and significantly reduced the reoccurrence of heart attack in patients with DM. Conclusions:In DM combined with ACS patients with rapid metabolizing type, the choice of different P2Y12 inhibitors after PCI had no significant effect on their prognosis. In DM combined with ACS patients with moderate-slow metabolizing type, tegretol not only significantly reduced the incidence of MACE, revascularization, and reinfarction, but also did not increase the risk of major bleeding. In terms of reducing the reoccurrence of heart attack, the benefit of using tegretol in the DM patients was greater than in the non-DM patients.

Relationship between clopidogrel responsiveness and CYP2C19 genotype by thromboelastography in patients with coronary heart disease after PCI / 中国输血杂志

【Objective】 To explore the relationship between clopidogrel responsiveness and CYP2C19 gene polymorphism by thromboelastography(TEG) after PCI in patients with coronary heart disease, and its guiding significance for the use of clopidogrel after PCI. 【Methods】 A total of 246 patients who underwent PCI surgery in our hospital from June 2018 to May 2021 and routinely took clopidogrel maintenance treatment after the operation were selected.The platelet inhibition rate of the patients was detected by TEG to obtain their response to clopidogrel.The CYP2C19 genotype was detected, and the relationship between the patient′s responsiveness to clopidogrel and the CYP2C19 genotype was analyzed. 【Results】 The CYP2C19 genotypes in 246 patients were fast metabolizer (n=95), intermediate metabolizer (n=104) and slow metabolizer (n=47), with the mean ADP inhibition rate(%) at 46.27±21.41, 40.99±25.53 and 24.77±21.68, respectively.They were divided into clopidogrel resistant group (n=98) and clopidogrel normal response group (n=148). The three groups of patients with different CYP2C19 genotypes had no statistically significant differences in gender composition, age and platelet count (P>0.05), while significant differences in hypertension, diabetes and hyperlipidemia(P0.05), but they were all lower than those with slow metabolism patients (both P0.5). Statistically significant difference was noticed in the low responsiveness to clopidogrel by different CYP2C19 genotypes (P<0.05). The drug responsiveness of clopidogrel measured by TEG had strong correlation with the patient′s CYP2C19 genotype.When the ADP inhibition rate was the best cut-off value (27.10%), the sensitivity and specificity of CYP2C19 genotype being diagnosed as the slow metabolite type, was 73.37% and 70.21%, respectively. 【Conclusion】 The response of clopidogrel after PCI in patients with coronary heart disease is associated with CYP2C19 genotype polymorphism.The use of TEG to detect the ADP inhibition rate of patients has strong predictive effect on CYP2C19 genotype and has guiding significance on antiplatelet therapy in patients with coronary heart disease after PCI.

Effect of CYP2C19 gene polymorphism on clopidogrel concentration, platelet inhibition rate and safety in patients after PCI / 药学实践杂志

Objective To explore the effect of CYP2C19 gene polymorphism on clopidogrel plasma concentration, rate of platelet inhibition and safety. Methods We screen the patients who took clopidogrel after PCI in our hospital, according to the inclusion and exclusion criteria. Blood samples were collected on the 6th day after clopidogrel administration. Clopidogrel blood concentration was determine by RP-HPLC. The CYP2C19 genotype was detected by non-amplified immune hybridization. The rate of platelet inhibition was evaluated by the thromboelastogram. The results were analyzed by SPSS 20.0 software. Results A total of 87 patients were recruited, including 46 males and 41 females. Among them, 34 cases were fast metabolism. 38 cases were medium metabolism. 15 cases were slow metabolism. The result showed that there was no significant difference in drug concentration between fast and intermediate metabolism(P=0.667). There was a significant difference in drug concentration between slow metabolism and fast metabolism or medium metabolism(P<0.05). Analysis of variance and chi-square test showed that CYP2C19 gene polymorphism has a significant effect on clopidogrel platelet inhibition rate and safety (P<0.05). Conclusion Guiding clopidogrel clinical medication based on CYP2C19 genotype alone does not necessarily achieve better therapeutic effects. CYP2C19 genotype detection and blood concentration monitoring can be combined to guide the clinical individualized administration of clopidogrel

Analysis of CYP2C19 gene polymorphism in patients with upper digestive system diseases in Anhui Province / 预防医学

Objective@#To analyze the CYP2C19 gene polymorphism in patients with upper digestive system diseases in Anhui Province, so as to provide evidence for individual treatment.@*Methods@#The 307 patients with upper digestive system diseases in the Department of Gastroenterology, The 901st Hospital of Combined Service Force of People＇s Liberation Army were selected. The CYP2C19 genotypes were detected by DNA microarray microarray. The CYP2C19 genotypes and metabolic types in different genders, ages and diseases were analyzed.@*Results@# There were 197 males ( 64.17% ) and 110 females ( 35.83% ) , with the age of ( 58.00±16.13 ) years old. The gene frequency of CYP2C19*1, CYP2C19*2 and CYP2C19*3 was 62.70%, 32.25% and 5.05%, respectively. There were 119 cases (38.76%) of *1/*1 ( 636GG, 681GG ), 129 cases ( 42.02% ) of *1/*2 ( 636GG, 681GA ) , 18 cases (5.86%) of *1/*3 ( 636GA, 681GG ) , 29 cases ( 9.45% ) of *2/*2 ( 636GG, 681AA ) , 11 cases ( 3.58% ) of *2/*3 ( 636GA, 681GA ) , and 1 cases ( 0.33% ) of *3/*3 ( 636AA, 681GG ). In terms of metabolisms, there were 119 cases ( 38.76% ) of fast metabolism type, 147 cases (47.88%) of intermediate metabolism type and 41 cases (13.35%) of slow metabolism type. There were no significant differences in CYP2C19 genotypes and metabolic types among the patients with different gender, age and digestive system diseases ( P＞0.05 ).@*Conclusion@#The CYP2C19 genotypes of patients with upper digestive system diseases were polymorphic, mainly the fast metabolism type and the intermediate metabolism type, which could provide reference for the clinical medication of individualized treatment of proton pump inhibitors.

Effects of Rabeprazole on the Pharmacokinetics of Clopidogrel and Its Active Metabolite in Healthy Volunteers with Different CYP2C19 Genotypes / 中国药房

OBJECTIVE：To investigate the effects of rabepr azole on the pharmacokinetic characteristics of clopidogrel and its active metabolite in healthy volunteers with different CYP2C19 genotypes. METHODS ：Healthy volunteers were selected as subjects，and then randomly divided into extensive metabolizer （EM）group，intermediate metabolizer （IM）group，and poor metabolizer（PM）group with 8 subjects in each group ，according to their CYP2C19 genotypes by random number table. In single-dose，randomized，open，two-cycle-crossover design ，each group was given Clopidogrel bisulfate tablets 300 mg or Clopidogrel bisulfate tablets 300 mg+Rabeprazole sodium enteric-coated tablets 20 mg. UPLC-MS/MS method was adopted to detect the concentration of clopidogrel and its active metabolite derivative （MP-H4）. The pharmacokinetic parameters were calculated and compared by DAS 2.0 software. RESULTS ：There was no statistical significance in clinical data as age ，height， body weight ，liver enzymes and serum creatinine among 3 kinds of metabolism subjects （P＞0.05）. Compared with subjects receiving clopidogrel alone ，cmax and AUC 0－t of clopidogrel of subjects combined with rabeprazole in EM group were increased by 36％ and 27％，while those of MP-H 4 were decreased by 34％ and 28％（P＜0.01）；cmax and AUC 0－t of clopidogrel of subjects combined with rabeprazole in IM group were increased by 19％ and 18％，while those of MP-H 4 were decreased by 19％ and 16％ （P＜0.05 or P＜0.01）；there was no statistical significance in cmax and AUC 0－t of clopidogrel and MP-H 4 in PM group after receiving rabeprazole additionally as well as tmax of clopidogrel and MP-H 4 in all metablism subjects ，compared with clopidogrel alone（P＞0.05）. CONCLUSIONS ：Among CYP2C19 EM and IM subjects ，combined use of rabeprazole can significantly increase the exposure of clopidogrel and decrease the exposure of its active metabolite MP-H 4，but has no significant impact on clopidogrel and its active metabolite in CYP2C19 PM subjects.

Correlation study between cytochrome P4502C19 gene polymorphism or metabolic type and ADP induced-platelet aggregation inhibition and clopidogrel resistance / 中国临床药理学与治疗学

AIM: To investigate the effect of the polymorphism and metabolic type of cytochrome P450 (CYP) 2C19 gene on the inhibitory rate of platelet aggregation induced by ADP and relationship with resistance of clopidogrel. METHODS: A total of 163 patients that are administrated with aspirin and clopidogrel were collected from the Yijishan Hospital of Wannan Medical College from June 2016 to July 2017. The CYP2C19*2, *3 and *17 genotypes of patients were detected with fluorescence staining in situ hybridization, according to the genotype, CYP2C19 enzyme activity was divided into fast metabolic (RM), intermediate metabolic (IM), slow metabolic (PM) and ultrafast metabolic type (UM). After 5 days of drug delivery, the platelet aggregation inhibition rate (IPAADP) induced by ADP was detected by thrombus elasto graph. IPAADP differences between CYP2C19*2, *3 and *17 genotype and CYP2C19 enzyme metabolic type were evaluated. CYP2C19 genotype and metabolic type as well as their distribution in clopidogrel resistance group (CR) and non clopidogrel resistance group (NCR) were observed. RESULTS: The mutation rates of CYP2C19*2, *3 and *17 were 30.98%, 6.75% and 1.23%, respectively. The average IPAADP was (67.03±26.79)% and the incidence of CR was 26.99%, and the IPAADP was (31.29±12.60)%. The IPAADP of CYP2C19*2 and *3 gene carriers were decreased significantly (P0.05). There was no statistical difference in the distribution of CYP2C19 genotypes and metabolic types in NCR and CR (P>0.05). CONCLUSION: CYP2C19 genotypes have significant effect on IPAADP, but there is no association with the occurrence of CR, and the related study needs to be further verified.

Effects of CYP2C19 gene polymorphism on the clinical prognosis of clopidogrel in elderly patients with acute cerebral infarction / 中国临床药理学与治疗学

AIM: To investigate the effect of CYP2C19 gene polymorphism on the clinical prognosis of elderly patients treated with clopidogrel who suffered acute cerebral infarction. METHODS: A total of 226 elderly patients with acute cerebral infarction who received aspirin and clopidogrel were prospectively enrolled in this study. The CYP2C19 genotype was detected by DNA microarray chip method. Based on CYP2C19 genotypes, the patients were divided into fast metabolism group, medium metabolism group and slow metabolism group. The National Institutes of Health Stroke Scale (NIHSS) scores before and after treatment were recorded. The changes of NIHSS scores before and after treatment were studied by repeated measurement ANOVA (analysis of variance), the decrease of NIHSS scores before and after treatment was used as the standard to evaluate the prognosis of patients, and the difference of favorable prognosis rate was compared among the three groups. Binary logistic regression analysis was used to explore the prognosis influencing factors of acute cerebral infarction, and adverse drug reactions (ADR) were observed in the three groups. RESULTS: There were 81 patients (35.8%), 108 patients (47.8%) and 37 patients (16.4%) in fast metabolism group, medium metabolism group and slow metabolism group, respectively, with a favorable prognosis rate of 86.4%, 73.1% and 64.9% respectively. There was significant difference in the favorable prognosis rate among the three groups, and fast metabolism group was significantly higher than slow metabolism group (P0.05). CONCLUSION: CYP2C19 gene polymorphism has an effect on the clinical prognosis of elderly patients treated with clopidogrel who suffered acute cerebral infarction, and the therapeutic effect on rapid metabolizer is better than that of slow metabolizer.

Evaluation of the relationship between the platelet reactivity detected by two methods and CYP2C19 gene polymorphism in patients with ACS after receiving clopidogrel / 解放军医学杂志

Objective To evaluate the relationship between the platelet reactivity detected by two methods and CYP2C19 gene polymorphism in patients with ACS after taking clopidogrel, and analyze the correlation between different platelet detection methods. Methods Forty-three patients with ACS, admitted in the General Hospital of Northern Theater Command from July to October 2019, met the diagnostic criteria and received dual antiplatelet therapy, were enrolled in present study. The gene chip was used for CYP2C19 genotype detection, vasodilatory stimulated phosphorylated protein (VASP) method and two revulsiveinduced phototurbidimetric methods [arachidonic acid-induced phototurbidimetry (AA-LTA), diphosphate adenosine-induced phototurbidimetry (ADP-LTA)] were used to evaluate the antiplatelet reactivity, and the correlation between different evaluation methods was compared. Results Of the 43 patients, 17(39.5%) were EMs, 19(44.2%) were IMs, and 7(16.3%) were PMs. The results of VASP were higher in PMs and IMs patients than those in EMs, and the results of AA-LTA were higher in PMs than those in IMs and EMs. The differences were significant (P<0.01). The platelet reactivity of VASP was positively correlated with AA-LTA and ADP-LTA (r=0.383, 0.369, P<0.05); and AA-LTA was positively correlated with ADP-LTA (r=0.496, P=0.011). Conclusions There is a difference between CYP2C19 gene polymorphism and platelet reactivity, and the correlation between VASP method and LTA method is low. CYP2C19 genotype can be used as a reference for the platelet reactivity of patients after clopidogrel therapy.

Clinical study on traditional Chinese medicine constitution types and CYP2C19 gene polymorphism in acute cerebral infarction / 国际中医中药杂志

Objective@#To investigate the correlation between Traditional Chinese medicine (TCM) constitution classification and clopidogrel-related CYP2C19 gene polymorphism of acute cerebral infarction patients.@*Methods@#A cross-sectional method was used in this study. Patients with acute cerebral infarction were screened and enrolled according to our inclusion and exclusion criteria. TCM constitution were evaluated in patients with acute cerebral infarction. Digital fluorescence hybridization Technology was used to test genotypes of CYP2C19 and Hardy-Weinberg’s equilibrium was used to examine CYP2C19 gene polymorphism of the patients. Binary logistic regression analysis method was used to explore the relationship between TCM constitution types and clopidogrel-related CYP2C19 gene polymorphism in acute cerebral infarction.@*Results@#Among the 100 patients with acute cerebral infarction, 18 belong to Yang-deficiency constitution (18 cases, 18%), 30 Yin-deficiency (30 cases, 30%), 18 belong to Qi-deficiency constitution (18 cases, 18%), 51 belong to phlegm-dampness constitution(51 cases, 51%), 14 belong to damp-heat constitution (14 cases, 14%), 2 belong to special constitution (2 cases, 2%), blood-stasis constitution (27 cases, 27%), Qi stagnation constitution (4 cases, 4%), and normal constitution (11 cases, 11%). The CYP2C19*2 gene polymorphism distribution: CYP2C19*2 (A/A, mutant homozygous) (21 cases, 21%), CYP2C19*2 (A/G, mutant heterozygote) (33 cases, 33%), CYP2C19*2 (G/G) (normal homozygous) (46 cases, 46%). The mutant allele frequency was 0.375. Binary logistic regression analysis showed that compared with A/A genotype, the G/G genotype of CYP2C19*2 in acute cerebral infarction was correlated with phlegm-dampness constitution (OR=5.105, 95% CI: 1.308-19.928, P<0.05) and blood-stasis constitution (OR=12.557, 95% CI: 1.741-90.558, P<0.05).@*Conclusions@#The proportion of phlegm-dampness constitution is the highest in patients with acute cerebral infarction. The mutation rate of clopidogrel-related CYP2C19*2 was significantly higher than that of CYP2C19*3 clopidogrel-related CYP2C19*2 gene polymorphism might be related to phlegm-dampness constitution and blood-stasis constitution.

Study on the Correlation between CYP2C19 Gene Polymorphisms and Antiplatelet Reactivity of Clopidogrel in Xinjiang Uygur Patients with Acute Coronary Syndrome / 中国药房

OBJECTIVE：To investigate the correlation between CYP2C19 gene polymorphisms and antiplatelet reactivity of clopidogrel in Xinjiang Uygur patients with acute coronary syndrome （ACS）. METHODS ：Totally 90 Uygur patients with ACS who were admitted to the cardiovascular department of Xinjiang Kashi Second People ’s Hospital from Jan. 2018 to Jan. 2019 were selected as the study subjects. They were given anti-platelet therapy of asprin+clopidogrel ，and received the treatment continuously for one year after discharge. The platelet aggregation inhibition （DPAI）rate of the patients were determined ，and the response to clopidogrel was evaluated. PCR-fluorescence probe method was used to detect genotype of CYP2C19*2 and * 3，and PCR-direct sequencing method was used to detect genotype of * 17. Multivariate Logistic regression analysis was adopted to investigate the correlation of gene and non-gene factors with DPAI of patients. RESULTS ：Among 90 patients，there were 10 patients with clopidogrel resistance （CR）and 80 patients with non-CR. There were 58，28 and 4 patients with CYP2C19*2 G/G，G/A，A/A genotype，respectively；there were 88 and 2 patients with CYP2C19*3 G/G，G/A genotype ，respectively；there were 64 and 26 patients with CYP2C19*17 C/C，C/T genotype ，respectively；the genotype frequency of each genotype was consistent with Hardy-Weinberg equilibrium （P＞0.05）. After treatment ，DAPIs of patients with CYP2C19*2 G/A，A/A genotype were decreased significantly，while those of the patients with A/A genotype were significantly lower than patients with G/A genotype patients （P＜ 0.05）. DAPIs of patients with CYP2C19*17 C/T genotype were increased significantly ，compared with C/C genotype 2016D01C087） patients （P＜0.05）. There was no statistical significance in @fudan.edu.cn DAPIs between CYP2C19*3 G/A and A/A genotype patients （P＞0.05）. Multivariate Logistic regression analysis showed 85775264@qq.com that CYP2C19 gene pol ymorphism was independently related to DPAI in Xinjiang Uygur patients with ACS [OR ＝2.314，95％CI（1.569，3.144），P＝0.009]，while age ，gender，smoking and other non-gene factors were not related to DPAI （P＞0.05）. CONCLUSIONS ：CYP2C19 gene polymorphism is associated with antiplatelet reactivity of clopidogrel in Xinjiang Uygur patients with ACS. * 2 wild type patients may have higher DPAI ，while * 17 wild type patients may have lower DPAI.

Effects of clopidogrel resistence and CYP2C19 genotype on the clinical prognosis of patients with acute coronary syndrome undergoing percutaneous coronary intervention / 中华心血管病杂志

Objective: To investigate the effects of clopidogrel resistence and CYP2C19 genotype on the clinical prognosis of acute coronary syndrome(ACS) patients undergoing percutaneous coronary intervention(PCI). Methods: This study was a retrospective cohort study. ACS patients who underwent PCI in Beijing Anzhen Hospital from October 2015 to January 2017 were recruited. The inhibition rate of adenosine diphosphate(ADP) was monitored by thromboelastography. All of these patients were divided into clopidogrel resistance and non-resistance group according to the monitoring results. CYP2C19 genotype was detected by TaqMan probe-based real-time quantitative PCR. Patients were divided into slow, medium and fast metabolic group, according to the CYP2C19 genotype. After 12 months of follow-up, the end points included all-cause death, cardiac death, angina, myocardial infarction, stent thrombosis, ischemic stroke and hemorrhage were collected. Combined thrombotic events were defined as a composite of angina, myocardial infarction, stent thrombosis and ischemic stroke. The differences of the incidence of clinical events between groups were compared. Cox regression was used to analyze the effects of clopidogrel resistance and CYP2C19 genotype on the combined thrombotic events, cardiac death and hemorrhage. Results: A total of 1 696 patients were included, and the age was (59.4±9.6) years, with 1 280(75.5%) males. There were 471 cases(27.8%) in clopidogrel resistance group, and 1 225 cases(72.2%) in clopidogrel non-resistance group. There were 218 patients(12.9%) were in slow metabolic group, 668(39.4%) in medium metabolic group, and 810 (47.8%) in fast metabolic group. The median follow-up time was 13.3 months, and 131 cases were lost to follow-up, with a loss follow-up rate of 7.7%. Compared with the clopidogrel non-resistance group, the clopidogrel resistance group had a higher incidence of myocardial infarction(7.6%(36/471) vs. 5.1%(62/1 225), P=0.041), a lower incidence of hemorrhage (13.2%(62/471) vs. 17.9%(219/1 225), P=0.020) and minor hemorrhage(11.5%(54/471) vs. 15.8% (194/1 225), P=0.022). There were no statistically significant difference in all-cause death, cardiac death, angina, stent thrombosis, ischemic stroke and severe bleeding between clopidogrel resistance and non-resistance group(all P>0.05). There was no statistically significant difference in the incidence of endpoint events among different CYP2C19 genotypes (all P>0.05). Cox regression analysis showed that clopidogrel resistance was an independent factor of combined thrombotic events (OR=2.334, 95%CI 1.215-4.443, P=0.016) and bleeding events (OR=0.481, 95%CI 0.174-0.901, P=0.023). While CYP2C19 genotype was not independent factor for combined thrombotic events, cardiac death and hemorrhage (all P>0.05). Conclusion: For ACS patients after PCI, clopidogrel resistance can increase the risk of combined thrombotic events, but also reduce the risk of bleeding; while CYP2C19 genotype is not an independent factor for clinical prognosis.

Association of CYP2C19*2 polymorphism with clopidogrel resistance among patients with high cardiovascular risk in Northeastern Mexico / Asociación del polimorfismo CYP2C19*2 con resistencia a clopidogrel en pacientes con alto riesgo cardiovascular en el noreste de México

abstract Objective: Oral antiplatelet drugs are a key to modern pharmacotherapy in cardiovascular atherothrombotic diseases. Clopidogrel (CLO) constitutes the main preventive treatment of atherothrombosis. However, a considerable inter-individual variation in CLO response has been documented, resulting in suboptimal therapy and an increased risk of recurrent adverse effects in some patients. The enzyme CYP2C19 has been reported to be the CYP isoform that activates CLO to its active metabolite. Several single nucleotide polymorphisms in the CYP2C19 gene have been identified as strong predictors of CLO-impaired pharmacological response. At least 16 variants have been associated with changes in CYP2C19 activity. Materials and Methods: The following research was composed of a total of 102 subjects with high cardiovascular risk in the northeast of Mexico, with a maintenance dose of 75 mg of CLO per day. The platelet reactivity was measured with VerifyNow P2Y12 assay, while the presence of CYP2C19*2 was identified by real-time polymerase chain reaction. Results: Patients were categorized by CYP2C19 metabolizer status based on *2 genotypes using the common consensus star allele nomenclature as normal metabolizer (G/G), intermediate metabolizer (G/A), and poor metabolizer (A/A), respectively. The phenotype frequency for CYP2C19*2 was 74.5% (G/G), 21.6% (G/A), and 3.9% (A/A). The subjects with the A allele presented ≥235 P2Y12 reaction unit levels, classifying them how poor metabolizer. The prevalence of reduced CLO effectiveness was associated with the presence of CYP2C19*2 polymorphism among Mexican patients. Conclusion: The presence of the CYP2C19*2 allele is related to resistance to the antiplatelet effect of CLO (p = 0.003).

Resumen Objetivo: Los antiplaquetarios orales son clave en la farmacoterapia moderna de las enfermedades aterotrombóticas cardiovasculares. Clopidogrel (CLO) constituye el principal tratamiento preventivo de aterotrombosis (AT). Sin embargo, se ha documentado una considerable variación interindividual en la respuesta a CLO, lo que da como resultado una terapia subóptima y mayor riesgo de efectos adversos en algunos pacientes. La enzima CYP2C19 es la isoforma CYP que activa CLO a su metabolito activo. Se han identificado varios polimorfismos de un solo nucleótido en el gen CYP2C19 como fuertes predictores de respuesta farmacológica alterada a CLO. Al menos 16 variantes se han asociado con cambios en la actividad de CYP2C19. Método: Se reclutaron un total de 102 sujetos con alto riesgo cardiovascular del noreste de México, con dosis de mantenimiento de 75 mg de CLO/día. La reactividad plaquetaria se midió con el ensayo Verify Now P2Y12, la presencia de CYP2C19*2 se identificó mediante polymerase chain reaction en tiempo real. Resultado: Los pacientes fueron clasificados por el estado metabolizador CYP2C19*2 utilizando nomenclatura consenso, como metabolizador normal (G/G), metabolizador intermedio (G/A) y metabolizador pobre (A/A), respectivamente. La frecuencia del fenotipo para CYP2C19*2 fue 74.5% (G/G), 21.6% (G/A) y 3.9% (A/A). Los sujetos con alelo A presentaron ≥235 niveles P2Y12 reaction unit, clasificándolos como metabolizadores deficientes. La prevalencia de eficacia reducida a CLO se asoció con la presencia del polimorfismo CYP2C19*2 en pacientes mexicanos. Conclusiones: La presencia del alelo CYP2C19*2 se relaciona con resistencia al efecto antiagregante plaquetario del CLO (p = 0.003).

Correlation analysis between different genotypes of CYP2C19, ERCC2 and XRCC1 and pathological indexes of gastroesophageal reflux and hiatal hernia in Xinjiang / 中国医师杂志

Objective@#The aim of this study was to investigate the correlation between different genotypes of CYP2C19, ERCC2 and XRCC1 and clinical indexes of gastroesophageal reflux and hiatal hernia in Xinjiang.@*Methods@#The clinical data of 101 patients with gastroesophageal reflux and hiatal hernia clinically diagnosed by people′s hospital of Xinjiang Uygur Autonomous Region from January 2016 to December 2017 were prospectively studied, and Wilcoxon rank sum test was used to analyze the genotypes and relevant clinical indicators.@*Results@#There was statistically significant difference in the distance of hiatal hernia between patients with CYP2C19 containing A/A homozygous genotype and those with other two genotypes (A/G or G/G) (P<0.05), and there was statistically significant difference in intrabolus pressure (IBP) between patients with G/G homozygous genotype and those with A/G heterozygous genotype (P<0.05). Esophageal sphincter lower esophageal sphincter (LES) residual pressure, LES relaxation rate and percentage of invalid swallowing between patients with ERCC2 containing A/C heterozygous genotype and those with A/A homozygous genotype also has significant statistical difference (P<0.05). The more C contained in the genotype, the lower IBP maximum (on average), and this pattern has statistical significance (P<0.05); There was no statistical difference for all clinical indicators among different XRCC1 genotypes.@*Conclusions@#Different genotypes of CYP2C19 and ERCC2 are closely related to the clinical indexes of gastroesophageal reflux and hiatal hernia. CYP2C19 containing A/G or G/G genotype is correlated with gastroesophageal reflux disease (GERD) and the incidence of hiatal hernia. The population containing A/G and G/G genotypes of CYP2C19 may be with a high incidence of hiatal hernia. Homozygous G/G genotype may be a high risk factor for aggravating reflux esophagitis. A/C and C/C genotypes contained in ERCC2 genotype were correlated with the incidence of hiatal hernia. The more C bases contained in ERCC2 genotype, the greater the effect of reducing IBP, indicating that the more C bases contained in ERCC2 genotype may be negatively correlated with the prevalence of hiatal hernia.