| Objectives:In order to analyze the factors that affect oxcarbazepine(OXC) pharmacokinetics andprovide population pharmacokinetics (PPK) models which predict individuation dosage forpatients with epilepsy, we established the PPK models of oxcarbazepine through theanalysis of oxcarbazepine population characteristics in Chinese epileptic patients, andanalyze the discrepancy of model parameters.Methods:(1) To establish HPLC-UV method for determination of the active metabolite(10-monohydroxy derivative, MHD) of oxcarbazepine in human plasma. A SymmetryShiledTMRP18column (4.6×250mm,5m) was used, with the mobile phase ofacetonitrile:0.05%formic acid water (23:77) at the detection wavelength of214nm. Theflow rate was1.0mL·min-1and temperature was set at40℃. Plasma samples wereextracted by ethylacetate and analyzed after been concentrated.6-methoxysalicylic acidwas used as the internal standard.(2) To assess pharmacokinetic characteristics of OXC in healthy Chinese volunteers,twelve healthy subjects were enrolled in this study and all subjects were randomly dividedinto three groups, three males and one females in each group. Three groups wereadministered a single dose of OXC tablet150mg、300mg and450mg for single-dosestudy.The300mg group was also for multiple-dose study.(3) We measured concentrations of MHD from108blood samples of78epilepticpatients, and all corresponding clinical data were collected from the medical records of thepopulation. The plasma MHD concentrations were measured by HPLC-UV. Populationpharmacokinetics analyses were performed using the nonlinear mixed-effect model(NLME) program. The basic pharmacokinetic models were best described assingle-compartment pharmacokinetic model with first-order absorption and elimination. The inter-individual variability was best described as exponential model andintra-individual variability was additive model. A number of covariates includingdemographic characteristics, hematological index, liver and renal function index werescreened for their influence on the pharmacokinetic parameters of MHD. Bootstrap wasapplied to the raw data as internal validation. Another9MHD concentrations of theepileptic patients were estimated using the model as external validation.Results:(1) The calibration curve was linear in the range of0.4~40.0mg·L-1.The LLOQ was0.4mg·L-1. The specificity of the method is good.(2) The main pharmacokinetic parameters of MHD after single oral doses (150,300and450mg) were as follows: Tmaxwere (3.75±1.26) h、(4.25±0.96) h、(4.75±0.96) hrespectively; Cmaxwere (3.31±0.58) mg·L-1、(5.57±1.69) mg·L-1、(9.32±1.59) mg·L-1respectively; t1/2were (11.48±4.04) h、(10.2±1.97) h、(8.51±2.03) h respectively; AUC0-48were (39.2±3.82) mg·h·L-1、(99.6±34) mg·h·L-1、(187.9±25.7) mg·h·L-1respectively. Themain pharmacokinetic parameters for300mg multiple-dose study were as follows: Tmaxwas (4.50±1.29) h, Cmaxwas (15.04±3.88) mg·L-1, t1/2was (10.20±3.57) h, AUC0-48was(356.6±87.9) mg·h·L-1.(3) The final regression model of MHD was: CL=tvCL×(ALT/30)dCLdALT×edCLdSex0×eηCL, V=tvV×(BUN/4.76)dVdBUN×(HGB/140)dVdHGB×eηV, Ka=tvKa×eηKa, Tlag=tvTlag×(Age/37)dTlagdAge×eηTlag. It was found that ALT and Sex have a significant influenceon the clearance of MHD. BUN and HGB have an influence onapparent volume of distribution. Lag time was influenced by Age. The results of bootstrapresampling proved the internal validity. In external validation, the regression betweenpredictions and dependant variable is: DV=0.784×PRED+3.802(R=0.892).Conclusions: The oxcarbazepine population pharmacokinetics models’ covariatesincluded ALT、Sex、BUN、HGB and Age in Chinese epileptic patients. The models wouldprovide reference for oxcarbazepine individualization therapy in clinic for epilepticpatients. |
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