Study On Population Pharmacokinetics Of Pramipexole And Oganic Cation Transporter 2 808G>T Gene Polymorphisms In Patients With Parkinson's Disease

Objective1?To establish the population pharmacokinetics model of pramipexole in patients with Parkinson's disease and provide reference for clinical individual administration.2?To discuss the influence of oganic cation transporter 2 808G>T genetic polymorphisms on plasma concentration of pramipexole.3?To discuss the effect to plasma concentration of pramipexole complicating with amantadine.Method1?Simultaneous determination of pramipexole and amantadine by UPLC-MS/MS.2? Apply the classification technology of SNaPshotSingle Nucleotide Polymorphism (SNP) to identify OCT2 808G>T genotype.3?To collect thepatients with Parkinson's disease who received pramipexole therapy from outpatients, and record associative clinical date. Evaluate the age, gender, body weight, hepatorenal function, OCT2 808G>T genotype and drug combination effects on the clearance rate of pramipexole via nonlinear mixed effects mode.4?Using the graphic method and statistical method to judge the goodness of fit of the model, Normalized Predictive Distribution Error (NPDE) validation and external validation method were adopted to evaluate the reliability of the model.Result1?The established UPLC-MS/MS plasma concentrations of pramipexole, The regression equation of standard curve was Y1=0.0001685 xi+0.004131 (R2=0.995) In human plasma, the standard curves of amantadine was Y2=0.1127 X2-0.002549 (R2=0.998).The standard curves of pramipexole and amantadine were linear from 10-1200 pg·mL-1 and 0.7-700ng·mL-1, the overall ralative recoveries were rangedfrom 100.3%-106.0% with the intraand interday RSDs were both less than 9.8%.2?In this study, the number of the genotyping OCT2 808G>T is GG,82 cases (75.2%); GT,24 cases (22.0%); TT,3 cases (2.8%) in 109 cases of patients with Parkinson's disease.Genotype distribution was consistent with Hardy-weinberg equilibrium. 3?According to 162 trough concentrations of the 109 patients,establish the PPK final regression model of pramipexole as follow: Glomerular Filtration Rate (GFR) is the main factor affecting CL/F.4?Graphic method shows that the final model is better than the simple model, the steady rate verified by Bootstrap was 99.8%, relative deviation was less than 2.1%,NPDE test showed homogeneity of variance according with normal distribution. The external validation results shows that the model has higher accuracy and precision than the basic model.5?In this study, we have not been found both OCT2 808G>T genotype and combined with application of amantadine are impact factors on pramipexole plasma concentration.Conclusion1?The methodological validation shows strong specificity, high sensitivity and repeatability which can be used to determine pramipexole and amantadine simultaneously.2?GFR is the main factor affecting the apparent clearance of the population pharmacokinetics of pramipexole3?The PPK model of pramipexole in the study is of great stability and predictive ability, which could provide for clinical individualized administration.