Individual Administration Study Of Lamotrigine Given To Chinese Southern Epilepsy Patients Based On Pharmacogenomics

Background and ObjectiveEpilepsy is one of the most common chronic neuropathy.Lamotrigine(LTG)is a new generation of antiepileptic drugs,which is often used to treat all kinds of epilepsy of adults and children with or without valproic acid(VPA).But there is huge individual variation in the pharmacokinetics and pharmacodynamics of LTG,leading to difficult administration.Pharmacogenomics research reveals that genetic factors are one aspect of the important factors affect the pharmacokinetics and pharmacodynamics of LTG.At present,domestic and foreign research related to genetic polymorphisms of LTG mainly concentrated in drug metabolism enzymes(UGT1A4,UGT2B7)and transporter protein(P-gp).There is still lack of related pharmacogenomics study about the complete pharmacokinetic-pharmacodynamic channel.Additionally,the correlation between the related genetic polymorphism and LTG concentration and the curative effect is still uncertain.Population pharmacokinetic(PKK)model is one of the methods able to quantify dosing individually.But to date,no LTG-PKK study concerning about genetic factors and non-genetic factors together in Chinese epilepsy patients is reported.And it is still lack of an effective method to quantify dosing individually in Chinese epilepsy patients.In summary,this study will analyze the influence of genetic factors(UGT1A4142T>G?UGT1A4 70C>A?UGT2B7C-161T?UGT2B7 G211T/A?UGT287 T-430C?UGT2B7 A-900G?MDR1 C3435T?MDR1 C1236T?MDR1 G2677A/T?ABCG2 G-1592A?HNF1?C51G?HNF4?T-136C?SCN1A G3199A and SCN2A G56A)and non-genetic factors(including gender,age,weight,drug combination,etc.)on LTG blood concentration and efficacy when using valproic acid alone or combined;establish blood concentration prediction equation;find out the effective blood concentration of LTG;build a population pharmacokinetic model taking into account of genetic and non genetic factors and finally provide scientific reference to individual administration for southern Chinese epileptic patients.Methods1.To establish a high performance liquid chromatography tandem mass spectrometry determination method(HPLC/MS/MS)for LTG And the method was verified through seven aspects---specific,linear,quantitative limit,precision,accuracy,recovery rate of extraction and stability.2.Using PCR-RFLP and MALDI-TOF MS methods to detect genotypes;calculating the frequencies of genotypes;comparing the frequencies with other races.3.Based on Chinese southern adult and children epileptic patients,to discuss relationship of non-genetic factors and genetic factors and lamotrigine plasma concentration and efficacy,by using chi-square test,non-parametric test,correlation analysis and logistic regression analysis etc.And to establish blood concentration prediction equation;to find out the effective LTG blood concentration.4.To build a population pharmacokinetics model of LTG by using the NONMEM software to analyze the data of LTG concentration and evaluate parameters.Results1.HPLC/MS/MS detection method is established for lamotrigine,and the method is of short analysis time,high sensitivity,good repeatability.LTG steady-state blood drug concentration was detected in 50 cases of patients with epilepsy detection,initially showing combined use of valproic acid or carbamazepine had great effects on LTG concentration.2.The distributions of genotypes of UGT1A4?UGT2B7?MDR1?ABCG2?HNF1??HNF4??SCN1A and SCN2A of epilepsy patients are accord with Hardy-Weinberg balance.There are big statistic variations between our studied genotypes and other races'genotypes.3.This part clarifies the correlation of influencing factors and LTG concentration for Chinese adult epileptic patients when using LTG alone.(1)Only UGT2B7 T-430C and UGT2B7 A-900G have a significant impact on LTG concentration.LTG concentraion of UGT2B7-430 C allele carriers is higher than T allele ones(p=0.03),and LTG concentraion of UGT2B7-900 GG and GA type patients is higher than AA type patients(p=0.037).(2)As for non-genetic factors,only age has an impact on LTG concentration.The younger the patient is,the lower the concentration is,and the longer the maintenance dose is(p=0.001,r=0.298).(3)This study establishes concentration prediction equation when using LTG alone,considering the influence of UGT2B7 A-900G and other non-genetic factors(age,weight,daily dose).The equation is as follows:C=3.512+0.02*dailydose-0.057*weight+0.024*age-0.347*UGT2B7 A-900G(AA and GA type of UGT2B7 A-900G is 1,GG type is 0).4.This part clarifies influence of different factors on LTG drug plasma concentration,when Chinese southern epileptic children use valproic acid combined with LTG:(1)This study makes it clear that UGT1A4 142T>G has a significant impact on LTG concentration of Chinese Southern epileptic children.LTG concentration of pediatric patients carrying wild homozygous(UGT1A4 142TT)is lower than ones with mutation heterozygote(UGT1A4 142TG)and mutation homozygous(UGT1A4142GG)(p=0.001),and concentration of UGT1A4 142TT type patients is also lower than UGT1A4 142 TG and GG type.(2)As for non-genetic factors,age has an impact on LTG concentration.The younger the patient is,the lower the concentration is,and the longer the maintenance dose is(p=0.002,r=0.225).And VPA concentration also affects LTG concentration.The higher VPG concentration is,the higher the LTG concentration is,and the shorter the maintenance dose is(p=0.001,r=0.3).(3)This study establishes prediction equation for LTG concentration of Chinese southern pediatric patients,considering the impact of UGT1A4 142T>G and other non-genetic factors(weight,valproic acid concentration,daily dose).The equation is as follows:C=0.794+0.03*dailydose-0.057*weight+0.010*VPAconcentration+0.532*UGT1A 4 142T>G(TT genotype of UGT1A4 142 is 0,TG and GG is 1)5.This study clarifies the impact of various factors on LTG efficacy and the efficient concentration for Chinese southern epileptic children when using valproic acid combined:(1)This study makes it clear that when using VPA combined,the younger and the lighter the patient is,the worse the efficacy is(p=0.023,p=0.027).It is easier to get better efficacy for male than female(p=0.048).(2)LTG-CDR is correlative to treatment efficacy(p=0.031),whose effective concentration is more than 2 ?g/ml.And it's able to provide reference to individual medication for Chinese Southern epileptic children.6.This study build a PPK model of LTG The result shows that valproic acid and rifampin are the important factors to the clearance of LTG.The final model is as follows:CL = ?1-(1-?4.VPA)-(1 + ?5*RFP)· e?1 V??2·e?2 Ka=?3Conclusions1.LC/MS/MS detection method was established for lamotrigine,and the method is of short analysis time,high sensitivity,good repeatability,and applied to lamotrigine blood concentration real-time monitoring and pharmacokinetic study for children with epilepsy.2.When using LTG alone,only age has an impact on LTG concentration of Chinese southern epileptic children.The younger the patient is,the lower the concentration is.For the first time this study claries the influence of UGT2B7 T-430C and UGT2B7 A-900G on LTG concentration.We establish an equation for prediction of LTG concentration,which is suitable for guiding adult individualized administration.3.When using valproic acid combined,age and VPA concentration affects LTG concentration of Chinese southern epileptic children.The younger the patient is,the lower the concentration is.The higher the VPA concentration is,the higher the LTG concentration is.This study claries that UGT1A4 142T>G has a significant impact on LTG concentration of Chinese southern epileptic children.We establish an equation for prediction of LTG concentration,which is suitable for guiding pediatric individualized administration.4.When using valproic acid combined,the younger and lighter the patient is,the worse the treatment efficacy is.It is easier to get better efficacy for male than female.The effective LTG concentration is more than 2 ?g/ml when using valproic acid combined in children.5.This study build a PPK model of LTG,which reveals that valproic acid and rifampin are the important factors to the clearance of LTG.This model is representative,which can be using to quantify individualized dosing.