Analysis Of Hospital Medication For Hypertension And The Effect Of Gene Polymorphism On The Pharmacokinetics Of Nifedipine Controlled-release Tablets In Shanxi Healthy Volunteers

Objective:Investigate the prescription of hypertension drugs in a Class 1 and Grade A Hospital in Shanxi Province,analyze the drug combination and treatment of hypertension patients with different grades,ages and comorbidities,to investigate the rationality of drug use and the medication status of calcium antagonist.Through the study on the correlation between gene polymorphism and the pharmacokinetics of nifedipine controlled release tablets,the main genes affecting the metabolism of nifedipine controlled release tablets in local area were discussed,providing theoretical basis for the individualization of clinical medication of nifedipine controlled release tablets and improving the level of rational drug use.Methods:Part 1.Analysis of Medication Prescriptions for Hypertension in a Class 1 and Grade A Hospital in Shanxi Province1.Patient screening:Electronic medical records of hypertension patients in the hospital from 2017 to 2019 were collected retrospectively.Inclusion criteria:（1）Patients with hypertension as the main diagnosis and hospitalization;（2）Patients≥18 years old.Exclusion criteria:（1）Patients treated in emergency department;（2）Patients who died in the course of treatment;（3）Not taking any of the five first-line drugs,including angiotensin converting enzyme inhibitors（ACEI）,angiotensin receptor antagonists（ARB）,calcium channel blockers（CCB）,β-blockers（B-Rb）,and diuretics;（4）Belong to one of the following conditions:malignant hypertension,acute hypertension,critical hypertension,subacute hypertension,idiopathic hypertension;（5）Patients with incomplete information.The study was approved by the hospital ethics committee（ethics approval no:（2020）YX no.（170））without informed consent.2.Data collection:The basic demographic characteristics,therapeutic drugs,biochemical indicators and comorbidity of patients were collected through the inpatient medical record query system.According to the Guidelines for the prevention and treatment of Hypertension in China revised in 2018,the antihypertensive targets of different ages and different comorbid diseases were determined.A total of 11comorbidities were included,including diabetes mellitus,hyperlipidemia,hyperuricemia,hyperhomocysteine,peripheral atherosclerosis,heart failure,coronary heart disease,nephropathy,liver-related diseases,obesity,and sleep apnea hypopnea syndrome.They were divided into three groups by age:18-65 years old,66-79 years old and≥80 years old.Hypertension is classified into three grades:Grade I（systolic blood pressure140-159 mm Hg;diastolic blood pressure 90-99 mm Hg）,gradeⅡ（systolic blood pressure160-179 mm Hg;diastolic blood pressure 100-109 mm Hg）and gradeⅢ（systolic blood pressure≥180 mmhg;diastolic pressure≥110 mm Hg）.3.Statistical analysis:SPSS16.0 software was used for statistical analysis.Continuous variables are expressed as mean±standard deviation,using ANOVA,Bonferroni test is applied when the variances are homogeneous,Dunnett T3 test and Welch test are applied when the variances are uneven.The categorical variables were expressed as percentages and the Chi-square test was applied.Multifactor logistic regression analysis was used to evaluate the influencing factors associated with the efficiency of antihypertensives.P<0.05 means the difference is statistically significant.Part 2.The effect of gene polymorphism on the pharmacokinetics of nifedipine controlled-release tablets in Shanxi healthy volunteers1.Source of volunteers:Volunteers who participated in the September 2019 trial（a single-center,open,randomized,single-dose,two-cycle,two-sequence,crossover study was conducted in September 2019 to evaluate the bioequivalence of test preparation nifedipine controlled release tablets and reference preparation nifedipine controlled release tablets（baixindo（?））on healthy adult subjects in an fasting/postprandial state）.This study was approved by the ethics committee（ethics approval no.:（2020）YX no.（104））.All the volunteers signed informed consent.2.Source of pharmacokinetics and safety data:Pharmacokinetic data of volunteers taking the reference preparation nifedipine controlled-release tablet（Baixintron（?））orally is derived from the trial（a single-center,open,randomized,single-dose,two-cycle,two-sequence,crossover study was conducted in September 2019 to evaluate the bioequivalence of test preparation nifedipine controlled release tablets and reference preparation nifedipine controlled release tablets（baixindo（?））on healthy adult subjects in an fasting/postprandial state）and adverse events（AE）that were positive,probable or probable related to nifedipine controlled-release tablet intake.Positive,probable or probable AE is considered an adverse drug reaction to nifedipine controlled-release tablets.3.Genotyping:screening genes based on literature;Matrix assisted laser desorption ionization time of flight（MALDI-TOF）was used for genotyping on the Sequenom Mass ARRAY i PLEX（Sequenom,USA）platform,and TYPER 4.0 software was used to output genotyping results.For not covered by the above methods,first-generation RT-PCR system was used for genotyping（Nanjing Sequencing Service network of Biomechanics）.4.Statistical analysis:SPSS16.0 software was used for statistical analysis.Hardy-Weinberg equilibrium estimates were performed for all the analyzed variations.Continuous variables are expressed as mean±standard deviation,using ANOVA,Bonferroni test is applied when the variances are homogeneous,Dunnett T3 test and Welch test are applied when the variances are uneven.The categorical variables were expressed as percentages and the Chi-square test was applied.Factors with significant differences in univariate analysis were included in multiple linear regression for further analysis.P<0.05 means the difference is statistically significant.Results:Part 1.Analysis of Medication Prescriptions for Hypertension in a Class 1 and Grade A Hospital in Shanxi Province1.Analysis of disease control rate:the overall control rate of drugs on hypertension was 60.79%,and the control rates of monotherapy,double therapy,triple therapy and quadruple therapy were 70.08%,59.97%,56.27%and 45.23%,respectively（P<0.001）.The control rate of monotherapy was higher than that of combination therapy.2.Analysis of prescription rate:a total of 1734 hypertension patients were included in this study,the number of gradeⅠhypertension patients was 71（4.09%）;gradeⅡ410（23.64%）;gradeⅢ1253（72.26%）.The number of patients in 18-65 years old was 1046（60.32%）;66-79 years old 480（27.68%）;≥80 years old 208（12.00%）.With the increase of hypertension grade,the single drug prescription rate decreased（67.61%、49.51%、22.28%）,while the combination drug prescription rate increased（32.39%、50.49%、77.72%）,but this phenomenon was not reflected in different age groups.Regardless of grade or age,CCB was the most commonly used drug in monotherapy.The most commonly used combination is CCB and B-RB.3.Analysis of biochemical index:The creatinine and uric acid of gradeⅢhypertension patients were higher than those of gradeⅠandⅡ（P<0.001）.The creatinine of patients aged≤79 years was lower than that of patients aged≥80 years（P<0.01）,cholesterol,triglyceride,low density lipoprotein and uric acid in 18-65 years old group were higher than those in≥66 years old group（P<0.001）.4.Analysis of drug use for comorbidities:there were significant differences in comorbidities among different age groups（P≤0.001）,but this distribution difference was not significant among different levels of hypertension.There were statistically significant differences in hypertension drug prescriptions under different comorbidities（P≤0.001）.Patients with diabetes used CCB（32.76%）and ARB（26.11%）mostly,patients with heart failure used diuretics（30.98%）andβ-RB（23.61%）mostly,patients with coronary heart disease used CCB（20.92%）and ARB（25.44%）mostly,patients with nephropathy used CCB（32.63%）and ARB（20.92%）mostly,patients with nephropathy used CCB（32.63%）and diuretics（20.92%）mostly.5.Analysis of the factors influencing the efficiency of antihypertensives include gender,age,CCB and B-RB use,and comorbidities including diabetes mellitus and heart failure.The probability of reaching the standard was 0.64 times for male than female（P=0.004）,and 1.626 times higher for patients≥66 years old than those aged<66 years old（P=0.001）.In addition,patients without diabetes and heart failure were more likely to achieve blood pressure reduction goals than patients with（OR=0.108,P<0.001;OR=0.199,P<0.001）,patients who did not receive CCB,β-Rb treatment were significantly more likely to reach the target（OR=0.742,P=0.037;OR=0.768,P=0.032）.Part 2.The effect of gene polymorphism on the pharmacokinetics of nifedipine controlled-release tablets in Shanxi healthy volunteers1.Volunteer Information:A total of 44 volunteers were included in the trial（a single-center,open,randomized,single-dose,two-cycle,two-sequence,crossover study was conducted in September 2019 to evaluate the bioequivalence of test preparation nifedipine controlled release tablets and reference preparation nifedipine controlled release tablets（baixindo（?））on healthy adult subjects in an fasting/postprandial state）,33of whom（female,14;Male,19）signed informed consent to participate in the nifedipine gene polymorphism study.2.Pharmacokinetic and safety data:Pharmacokinetic parameters,such as area under blood concentration-time curve(AUC_0-t),peak concentration(C_max),apparent clearance rate（Cl/F）and half-life(t_1/2),were collected from 33 healthy volunteers.Common adverse reactions included neurological diseases（27.3%）,cardiac diseases（15.2%）and respiratory diseases（9.1%）.Other adverse reactions such as nausea,hypotension and polycythemia accounted for 3.0%,respectively.3.Effect of gene polymorphism on pharmacokinetics of nifedipine controlled-r elease tablets（1）Gene Metabolism-related:Subjects with CYP3A4 rs2242480 C/C genotypes exhibited a lower Cmax/DW than C/T and T/T individuals（40.61±9.73 vs 54.69±21.12kg*ng/mL*mg,P=0.049;40.61±9.73 vs 78.37 kg*ng/mL*mg,P=0.02）and a higher Vd/F than the T/T subjects（10.36±2.77 vs 4.98 L/kg,P=0.039）.ABCB1rs1045642A/A subjects exhibited a lower Tmax（10.61±7.82 vs 20.60±8.83 h,P=0.04）than G/G carriers.（2）Gene Pharmacodynamics-related:The Vd/F and t_1/2of the CACNA1D rs312481 G/G subjects was lower than that of the A/G carriers（8.40±3.33 vs 12.99±5.67 L/kg,P=0.002;6.39±1.45 vs 8.60±3.23 h,P=0.002）.The Cmax/DW and t1/2 of CACNA1C rs2238032 T/G carriers was lower than that of the T/T ca rriers（39.53±7.64 vs 53.71±21.04 kg*ng/mL*mg,P=0.027;6.71±2.41 vs 6.97±1.95 h,P=0.049）.ACE rs4646994,I/I subjects presented a higher Cmax/DW（59.87±21.23 vs 34.93±10.80 kg*ng/ml*mg,p=0.047）,a higher AUC0-t/DW and AUC0-∞/DW（1410.00±530.75 vs.730.30±234.92 kg*ng*h/ml*mg,p=0.041;1445.60±530.29 vs.742.96±235.72 kg*ng*h/ml*mg,p=0.037,respectively）,and a lower Cl/F（770.60±238.96 vs.1456.30±527.07 ml/h*kg,p=0.037）than D/D c arriers.I/I subjects exhibited a higher Tmax（19.75±8.35 vs.12.72±8.48 h,p=0.031）,and a higher Cmax/DW（59.87±21.23 vs.42.63±11.84 kg*ng/ml*mg,p=0.034）than D/I carriers.SLC14A2 rs3745009 T/T subjects were associated wit h higher Cmax/DW（68.18±18.46 vs 50.00±20.20 kg*ng/mL*mg,P=0.034;68.18±18.46 vs 40.95±10.55 kg*ng/mL*mg,P=0.025）,higher AUC0-t/DW（1665.20±569.96 vs 1231.10±530.71 kg*ng*h/mL*mg,P=0.04;1665.20±569.96 vs894.57±288.80 kg*ng*h/mL*mg,P=0.016）,higher AUC0-∞/DW 1727.00±579.44 vs 1265.20±523.35 kg*ng*h/mL*mg,P=0.049;1727.00±579.44 vs 909.64±292.68 kg*ng*h/mL*mg,P=0.014),lower Cl/F（640.88±227.23 vs 896.91±294.74 mL/h*kg,P=0.049;640.88 vs 1248.00 mL/h*kg,P=0.014）,and lower Vd/F（6.34±2.60 vs 9.23±3.55 L/kg,P=0.006;6.34±2.60 vs 11.09±4.83 L/kg,P=0.011）compared with C/C and C/T carriers.4.Effect of genetic polymorphism on safety:The incidence of adverse events was higher in women than in men（50%vs 42.1%）.The incidence of adverse reactions was statistically different among ADRB2 RS1042713 genotypes（G/G 12.5%,A/G 61.11%,A/A 42.8%;P=0.038）.CYP3A5 RS776746 is associated with the occurrence of headache and dizziness（A/A 50%,A/G 14.3%and G/G 50%;P=0.002）.Conclusion:1.In the hypertension treatment prescription of a Class 1 and Grade A Hospital in Shanxi province,the control rate of single drug on hypertension was higher than that of combination drug.The combination of antihypertensive drugs was mainly affected by hypertension grade,and calcium channel blockers were most used among different types of antihypertensive drugs2.The main genes that affect the metabolism of nifedipine controlled-release tablets are CYP3A4,ABCB1,ACE,SLC14A2.CYP3A4 rs2242480 mutation can i ncrease C_maxand slow down metabolism of nifedipine controlled release tablets.A BCB1 rs1045642 mutation can reduce T_maxand accelerate the metabolism of nifed ipine controlled release tablets.ACE rs4646994 mutation can increase C_maxand A UC_0-t,decrease Cl/F and slow down metabolism of nifedipine controlled release ta blets.SLC14A2 rs3745009 homozygous mutation can increase C_maxand AUC_0-t,d ecrease Cl/F,and slow down the metabolism of nifedipine controlled release tablet s.