Research On The Individualized Drug Administration Of Venlafaxine Based On CYP450 Gene Polymorphism And Therapeutic Drug Monitoring

ObjectiveIt was found that the dose-adjusted concentrations of venlafaxine varied widely among patients in therapeutic drug monitoring,which may cause ineffective treatment or adverse reactions in different patients at the same dosage.To promote the rational use of venlafaxine and reduce the adverse reactions,this study aims to explore the effect of gender,age,smoking,drinking,dosage forms,liver enzymes?ALT,AST?,BMI,concomitant medication,combined diseases,CYP2D6 and CYP2C19 genotypes on C_VEN/D,C_ODV/D and C_total/D.The population pharmacokinetic parameters of venlafaxine in healthy volunteers were calculated to help establish the of population pharmacokinetic model of venlafaxine in patients with depression,which can provide references for clinical individualized medication.Method?1?The clinical serum samples were treated with protein precipitation using acetonitrile as a precipitant,and were determined by high performance liquid chromatography tandem mass spectrometry?LC-MS/MS?.The column was Agilent XDB C18?4.6 mm×50 mm,1.8?m?,and the mobile phase was methanol-water?90:10,v/v,containing 2 mmoL·L^-11 ammonium formate?.The flow rate was 0.70 mL·min^-1,the column temperature was 35 ^OC,the injection volume was 1?L,and the electrospray ionization source is used.The multi-reaction monitoring mode was used to quantitatively analyze the ionization pairs as m/z 278.15?58.20?VEN?,m/z 284.15?58.20?VEN-d6?,m/z 264.10?58.10?ODV?,m/z 270.10?58.10?ODV-d6?.?2?The possible factors with regard to the uncertainty were analyzed,including weighing of standard substances,preparation of standard solutions,preparation of serum samples,tolerance of instruments,repeatability,matrix effect,extraction recovery and linearity.?3?Information of patients meeting the inclusion and exclusion criteria were collected.The effects of gender,age,CYP2D6 genotype,CYP2C19 genotype,smoking,drinking,dosage form,liver enzymes?ALT,AST?,BMI,combined medication and combined diseases on C_VEN/D,C_ODV/D and C_total/D were analyzed using SPSS16.0software,and the regression models of C_VEN/D,C_ODV/D,and C_total/D were established.?4?The bioequivalence test data of venlafaxine in healthy volunteers were collected to establish a population pharmacokinetic model for venlafaxine and population values of population pharmacokinetic parameters were calculated using NONMEN software.Results?1?The standard curve of venlafaxine is y=1.55044 x+0.00016?R²=0.9995?,the linear range is 4?400 ng·mL^-1.the standard curve of O-desmethylvenlafaxine is y=1.42131 x-0.03608?R²=0.9991?with a linear range of 20?2000 ng·mL^-1.Except for the inter-assay precision of the lower limit of venlafaxine was 15.33%,the inter-assay and intra-assay precisions were between 0.83%and 8.73%.The accuracies were between97.36%and 101.8%,and the average extraction recoveries were greater than 95.67%,and the stability is good.?2?The expanded uncertainty of venlafaxine were 0.847ng·mL^-1,7.518 ng·mL^-1and20.776ng·mL^-11 at low(12 ng·mL^-1),middle(120 ng·mL^-1)and high(300 ng·m L^-1)concentrations,respectively;for O-desmethylvenlafaxine,the expanded uncertainty were11.666 ng·mL^-1,91.479 ng·mL^-11 and 254.523ng·mL^-11 at low(60ng·m L^-1),middle(600ng·mL^-1)and high(1500 ng·mL^-1)concentrations respectively?P=95%,k=2?.?3?C_VEN/D may be affected by creatinine clearance,combined hypertension,combined hypokalemia,CYP2D6,and CYP2C19 genotypes,and is related to CYP2D6genotypes and whether combined with hypertension?P<0.05?.CODV/D may be affected by gender,creatinine clearance,BMI,and combined quetiapine in the body,and is related to gender and whether quetiapine is combined?P<0.05?.C_total/D may be affected by gender,creatinine clearance and CYP2C19 genotype,and is related to whether it is CYP2C19 PM?P<0.05?.C_VEN/D and C_total/D have certainly accuracy for predicting whether the patient is CYP2C19 PM.The area under ROC curves were 0.743 and 0.725,and optimal thresholds were 0.903 and 1.890 ng·mL-1·mg-1·d.?4?One-compartment model has a good goodness-of-fit for the data.The population pharmacokinetic parameters were V=78.80 L,CL=104.00 L·h^-1,and Ka=0.117 h^-1.Conclusion?1?The method is simple,sensitive,specific and suitable to monitor the concentrations of venlafaxine and O-desmethylvenlafaxine in human serum.?2?The uncertainty in the determination of venlafaxine and O-desmethylvenlafaxine in human serum by LC-MS/MS was mainly related to calibration curve fitting,matrix effect and extraction recovery.The selection of an appropriate concentration level of internal standard can effectively reduce the uncertainty of calibration curve.?3?In female patients,patients with low creatinine clearance or CYP2C19 PM treated with venlafaxine,it is improtant to reduce the dose of venlafaxine appropriately.Therapeutic drug monitoring was recommended to reduce the incidence of adverse reactions.?4?The population pharmacokinetic model in healthy volunteers was stable and reliable,which can provide a reference for establishing the patient's venlafaxine population pharmacokinetic model.