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.

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.

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.

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.

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.

Correlation between CYP2C19 gene polymorphism and clinical efficacy of compound danshen dropping pills in treatment of senile coronary atherosclerotic heart disease / 中国中西医结合急救杂志

Objective To study the correlation between the polymorphism of CYP2C19 gene and the clinical efficacy of compound Danshen dripping pills in treatment of senile coronary atherosclerotic heart disease (CHD) and to provide theoretical basis for rational drug use. Methods Two hundred and six elderly patients with CHD treated in the Third Hospital of Hebei Medical University from June 2015 to December 2017 were screened for genotype detection and classification. All patients were given oral compound Danshen dripping pills, 10 pills each time, 3 times a day, for consecutive 2 months. Serological indexes, electrocardiograph (ECG) monitoring, liver and kidney function testing were performed before and after treatment to evaluate drug efficacy and adverse reactions. Results In senile patients with CHD, after taking compound danshen dripping pills for 2 months, the efficacy in patients with intermediate metabolizer (IM) was more significantly effective than the efficacies of the patients with extensive metabolizer (EM) and poor metabolizer (PM) [clinical efficacy: 95.6% (87/91) vs. 80.5% (33/41), 93.2% (69/74), ECG efficacy: 95.6% (87/91) vs. 78.0% (32/41), 94.6% (70/74)], at the same time, the serum levels of triglyceride (TG) and high-density lipoprotein (HDL) in patients with IM were also higher than those in patients with PM and EM [TG (mmol/L): 1.33±0.52 vs. 1.33±0.41, 1.33±0.27, HDL (mmol/L): 1.58±1.17 vs. 1.44±0.65, 1.38±0.18], and the levels of total cholesterol (TC), low-density lipoprotein (LDL) and hypersensitive C-reactive protein (hs-CRP) were lower than those of PM and EM [TC (mmol/L): 3.48±0.25 vs. 3.56±0.96, 3.51±0.51, LDL (mmol/L): 2.19±0.35 vs. 2.23±0.49, 2.21±0.87, hs-CRP (mg/L): 3.50±1.07 vs. 3.53±1.51, 3.54±2.01]. The incidences of adverse reactions in patients with EM and IM were significantly lower than the incidence of PM [6.8% (5/74), 9.9% (9/91) vs. 31.7% (13/41)], the differences being statistically significant (both P < 0.05). Conclusions CYP2C19 gene polymorphism is closely related to C HD in elderly, in such patients with IM, after taking compound Danshen dripping pills, the efficacy is significant and has low incidence of adverse reactions. Therefore, in the course of clinical treatment of elderly patients with CHD, genetic testing should be carried out to fully consider the influence of CYP2C19 gene polymorphism on the efficacy of the pill, and adopting personalized therapy can increase efficacy and reduce toxicity.

Correlation between efficacy of Ticagrelor and CYP2C19 gene polymorphism in patients with diabetes mel-litus complicated with acute coronary syndrome receiving PCI / 实用医学杂志

Objective To study the CYP2C19 genotype in patients with acute coronary syndrome(ACS) complicated with diabetes mellitus(DM)receiving percutaneous coronary intervension(PCI)by polymerase chain reaction(PCR),and to evaluate the efficacy of Ticagrelor in CYP2C19 gene polymorphism. Methods A total of 494 ACS patients with DM were enrolled. The patients were divided into routine treatment group and individual treatment group. Routine treatment group received 0.1 g/d aspirin/d and 75 mg/d of Clopidogrel. CYP2C19 gene polymorphism was examined in individual treatment group.(*1/*1)was classified into fast metabolic type,mutant heterozygous type(*1/*2,*1/*3)into intermediate metabolic type and mutant pure type (*2/*2,*2/*3,*3/*3) into slow metabolic type. Fast metabolic type received aspirin 0.1 g/d and Clopidogrel 75 mg/d,and intermediate and slow metabolic type received aspirin 0.1 g/d and Ticagrelor 90 mg bid for 12 months or more to observe the inci-dence of adverse cardiovascular events ,bleeding and other adverse reactions in 2 groups. Results The incidence of cardiac death ,recurrent myocardial infarction and angina pectoris ,stroke ,stent thrombosis and target vessel revascularization in routine treatment group was significantly higher than that in individual treatment group(P <0.05). There was no significant difference between two groups in terms of major bleeding and secondary bleeding (P > 0.05). The minimum bleeding rate was slightly higher in intermediate metabolic type in individual treatment group but without significantly difference when compared with that in fast metabolic type and slow metabolic type (both P>0.05). Conclusion Without elevating the risk of bleeding within 12 months,the efficacy of Ticagrelor is not affected by CYP2C19 gene polymorphism in patients with ACS complicated with DM after PCI.

Correlation between efficacy of Ticagrelor and CYP2C19 gene polymorphism in patients with diabetes mel-litus complicated with acute coronary syndrome receiving PCI / 实用医学杂志

Objective To study the CYP2C19 genotype in patients with acute coronary syndrome(ACS) complicated with diabetes mellitus(DM)receiving percutaneous coronary intervension(PCI)by polymerase chain reaction(PCR),and to evaluate the efficacy of Ticagrelor in CYP2C19 gene polymorphism. Methods A total of 494 ACS patients with DM were enrolled. The patients were divided into routine treatment group and individual treatment group. Routine treatment group received 0.1 g/d aspirin/d and 75 mg/d of Clopidogrel. CYP2C19 gene polymorphism was examined in individual treatment group.(*1/*1)was classified into fast metabolic type,mutant heterozygous type(*1/*2,*1/*3)into intermediate metabolic type and mutant pure type (*2/*2,*2/*3,*3/*3) into slow metabolic type. Fast metabolic type received aspirin 0.1 g/d and Clopidogrel 75 mg/d,and intermediate and slow metabolic type received aspirin 0.1 g/d and Ticagrelor 90 mg bid for 12 months or more to observe the inci-dence of adverse cardiovascular events ,bleeding and other adverse reactions in 2 groups. Results The incidence of cardiac death ,recurrent myocardial infarction and angina pectoris ,stroke ,stent thrombosis and target vessel revascularization in routine treatment group was significantly higher than that in individual treatment group(P <0.05). There was no significant difference between two groups in terms of major bleeding and secondary bleeding (P > 0.05). The minimum bleeding rate was slightly higher in intermediate metabolic type in individual treatment group but without significantly difference when compared with that in fast metabolic type and slow metabolic type (both P>0.05). Conclusion Without elevating the risk of bleeding within 12 months,the efficacy of Ticagrelor is not affected by CYP2C19 gene polymorphism in patients with ACS complicated with DM after PCI.

Research on correlation between CYP2C19 gene polymorphism and clopidogrel curative effect in patients with coronary heart disease / 国际检验医学杂志

Objective To analyze and investigate the correlation between the CYP2C19 gene polymorphism and clopidogrel cura-tive effect in the patients with coronary heart disease (CHD) to provide valuable reference information for the future clinical work. Methods A total of 128 cases of CHD undergoing PCI in our hospital from January 2015 to January 2016 were selected as the re-search subjects.All of them were treated with clopidogrel ,the loading dose was 300mg ,and the maintenance dose was 75mg.The subjects were divided into the clopidogrel resistance group and response group.The drug-metabolizing CYP2C19 genotype was com-pared between the two groups and the effect of CYP2C19 genotype on the clopidogrel response was observed.Results Among the subjects ,27 cases were clopidogrel resistance.A total of 16 cases of CYP2C19 slow metabolic gene carriers were detected.There was statistically significant difference between the patients with chronic metabolic genotype VASP-PRI with fast metabolic geno-type and intermediate metabolic genotype(P<0.05).The incidence rate of adverse end point events had statistical difference be-tween the clopidogrel resistance group and clopidogrel response group(P<0.05).Conclusion In the risk factors of clopidogrel re-sistance ,slow metabolism CYP2C19 genotype and clopidogrel resistance will increase the risk of clinical adverse endpoint events oc-currence ,clinic should give adequate attention.

Study on the related factors with clopidogrel resistance of patients with acute cerebral infarction / 中国综合临床

Objective To study the effect of clopidogrel on different CYP2C19 genotypes and platelet reactivity in acute cerebral infarction patients with antiplatelet aggregation.Methods Four hundred and seventy-four cases of cerebral infarction patients in Beijing Tiantan Hospital Affiliated to Capital Medical University from April 2015 to April 2016 were collected.CYP2C19 genotype was determined,and the genotype was divided into the wild type group,the heterozygous type group and the mutant homozygous group.Platelet aggregation inhibition rate(ADP%) and platelet reactivity index induced by ADP were detected.Patients were divided into clopidogrel resistance group(group CR) and non resistant group according to whether ADP% was less than 30.SPSS 16.0 statistical software was used for statistical analysis,the comparison between groups using independent samples t test,chi square test and multivariate analysis using Logistic regression analysis,when P<0.05 difference was statistically significant.Results Among the 474 patients,204 cases(43.04%) were divided into wild-type group,and 204(43.04%) and 66(13.92%) were divided into the mutant heterozygous group and mutant homozygous group.In Chi square test analysis,clopidogrel resistance group and non resistance group CYP2C19 genotype distribution was significantly different(χ2=6.658,P=0.036).CR group angle(α) values((68.87±5.47)°) and MA((66.77±6.25) mm) were higher than that of CS group ((66.55±6.05)° and (63.30±5.66) mm,t=2.199,3.387,P=0.029,0.001).The multivariate logistic regression analysis showed that OR of angle level was 1.028,95%CI was 0.929-1.137 (P=0.595);OR of Ma level was 1.561,95%CI was 0.785-0.970 (P=0.012).Conclusion The effect of clopidogrel on platelet aggregation in patients with acute cerebral infarction is decreased by CYP2C19 gene mutation.CYP2C19 mutant allele is a risk factor for clopidogrel resistance.Angle (α) value and MA value are the risk factors for the diagnosis of CR in the patients with acute cerebral infarction,and the risk of clopidogrel resistance increased when the patients′ Angle (α) value and the value of MA increased.MA value as a predictor of CR and the screening tool has a certain value.