On The Construction Of A Dose Prediction Model For Lamotrigine In Women With Epilepsy During Pregnancy Based On Gene Polymorphism And Estrogen Spectrum

Objective:Lamotrigine(LTG)is one of the most widely used antiepileptic drugs(AEDs)in monotherapy for women of childbearing age and perinatal period.It is also the most well-studied and well-documented AED for the treatment of epilepsy during pregnancy.A series of physiological changes such as weight gain,hemodynamic changes and high estrogen status in pregnant women can significantly change the pharmacokinetic behavior of LTG.The rapid increase of clearance rate during pregnancy can reduce the serum concentration of LTG to below the target concentration,leading to an increased risk of epileptic seizures.The purpose of this study was to characterize the pharmacokinetic changes of LTG from pre-pregnancy to late postpartum,to determine the predictors of increased risk of seizures,and to explore the intrinsic factors that led to changes in LTG clearance rate during pregnancy based on the construction of a population pharmacokinetic model.Then,this model combined with the Bayesian feedback method can accurately estimate the individual pharmacokinetic parameters of patients and establish an individualized dose prediction model of LTG for patients with epilepsy during pregnancy in order to promote clinical scientific and rational drug use.Methods: 1.Pharmacokinetic changes of LTG during pregnancy and application of therapeutic drug monitoring The clinical records of pregnant women with epilepsy who were treated with LTG monotherapy and had regular therapeutic drug monitoring in the Department of Neurology,Shengjing Hospital of China Medical University from January 2016 to November 2019 were collected.The apparent clearance(CL/F)and the ratio to target concentration(RTC)were calculated for each trimester.RTCs were compared between patients with and without an increase in the frequency of seizures to evaluate the relationship between LTG serum concentration and frequency of seizures during pregnancy.The RTC threshold which can predict the increase of seizure frequency during pregnancy was determined by the receiver working characteristic curve(ROC curve).Appropriate statistical analysis were performed by SPSS software version 22.0.For quantitative data,normal distribution of the variances was tested by Shapiroe-Wilk normality test before statistical analysis.Multiple comparisions were made using One-way Univariate Analysis of Variance(ANOVA)with LSD’s test for normal distributed data.Pairwise comparisons were made by Student’s t-test or Manne Whitney U test with two-tailed distribution.For qualitative data,chi-square test was used.A P value < 0.05 was considered statistically significant.2.On the construction of a dose prediction model for LTG in women with epilepsy during pregnancy based on gene polymorphism and estrogen spectrum The clinical records of pregnant women with epilepsy who were treated with LTG and had regular therapeutic drug monitoring in the Department of Neurology,Shengjing Hospital of China Medical University from January 2016 to November 2019 were collected.The MALDI-TOF/MS method was used to detect 29 SNPs(UGT1A4(rs3732218,rs3732219,rs2011425,rs8330,rs1042640),UGT2B7(rs7668258,rs7438135,rs7439366,rs28365063,rs4356975),ABCB1(rs1128503,rs1045642,rs2032582),ABCG2(rs2231142,rs2231137),SLC22A1(rs628031,rs2282143),SLCO1B1(rs4149056),ZNF423(rs9940645),CYP19A1(rs10046,rs4646,rs700519),ESR1(rs2234693,rs9340799,rs728524,rs3798577),ESR2(rs1256030,rs1256065,rs1255998))genotypes.The genotype frequencies of the above SNP sites were determined whether they were consistent with Hard-Weinberg equilibrium by Haploview4.2 software.The concentrations of estrone(E1),estradiol(E2)and estriol(E3)in serum were determined by electrospray ionization quadrupole time-of-flight mass spectrometry(ESI-Q-TOF/MS).The non-linear mixed effect model(NONMEM)was used to establish the population pharmacokinetic model for LTG in pregnant women with epilepsy.It was used to investigate the effect of covariates such as physiological and pathological indexes,concomitant medications and gene polymorphism on pharmacokinetic parameters of patients.The goodness of fit method,the normalized prediction distribution error(NPDE)test and the bootstrap method were performed to evaluate the stability and credibility of the final model.On the basis of the population pharmacokinetic model for LTG in pregnant women with epilepsy,the JPKD-LTG dose prediction model was established through the user-defined Bayesian module(UDBM)of the Java PK for Desktop software(JPKD,version 3.1).The weighted deviation(WRES)between the predicted concentration(ρprediction)and the observed concentration(ρobservation)was calculated to evaluate the prediction capability of the JPKD-LTG dose prediction model.Results : 1.Pharmacokinetic changes of LTG during pregnancy and application of therapeutic drug monitoring In this study,the clinical records of 49 pregnant women with epilepsy were screened,and a total of 26 patients were excluded because they did not meet the inclusion criteria.A retrospective analysis of 282 blood concentration monitoring of 23 pregnant women with epilepsy who were treated with LTG monotherapy showed that apparent clearance increased by 105.23% during the first trimester(P = 0.0014),202.85% during the second trimester(P < 0.0001),and 201.11% during the third trimester(P < 0.0001)compared with the pre-pregnancy level,and the peak appeared in the middle and late stages of pregnancy.Clearance decreased rapidly on the day of delivery and gradually returned to the pre-pregnancy level at 6 weeks after delivery.Ten patients who had adequate baseline information were included to examine the association between serum LTG concentration and seizure frequency.The RTC values of patients with and without an increased frequency of seizures were significantly different(P < 0.0001),and increased seizure frequency was associated with a lower RTC.An RTC < 0.62 was a predictor of deteriorating seizures.2.On the construction of a dose prediction model for LTG in women with epilepsy during pregnancy based on gene polymorphism and estrogen spectrum The one-compartment and first-order absorption model was used to fit the collected data of 317 sampling points of 49 pregnant women with epilepsy by NONMEM software,and the exponential model and the combined model were used to estimate the individual variation and residual variation of each parameter,respectively.The influence of each factor on the pharmacokinetic parameters was investigated by stepwise covariate modeling and the final model was as follows: CL/F(L/h)= 1.78×EXP(E2/1.80×0.226)×1.14Trimester=2×1.24Trimester=3×EXP(E3/3.472×(-0.0488))×EXP((E1/0.591-1)×(-0.0589))×(T AMT/150)0.357×1.12ABCB1 rs1128503 AG×0.326ABCB1 rs1128503 GG×1.51ZNF423 rs9940645 AG/GG,V/F(L)= 90×(TBIL/9.37)0.993.The population typical value of LTG CL/F during pregnancy was1.78 L/h and the typical value of V/F was 90 L.When estradiol concentration(E2)increased by 1ng/m L,LTG CL/F increased by 0.238 L/h,while estriol(E3)and estrone (E1)concentration increased by 1 ng/m L,LTG CL/F decreased 0.025 L/h and 0.005 L/h,respectively.ABCB1 rs1128503 homozygous mutant(GG genotype)can significantly reduce the LTG CL/F,which was only 32.6% of wild homozygous(AA genotype)and29.1% of heterozygous mutant(AG genotype).Patients with ZNF423 rs9940645mutation(AG/GG genotype)had CL/F of 2.69 L/h,which was 51% higher than that of wild homozygote(AA genotype).After verification of 50 steady-state blood samples outside the modeling group,the weight deviation(WRES)between the predicted concentration and the observed concentration was 9.54 ± 5.29%.The WRES of 28 blood samples(78%)was within ± 10%.The WRES of the 48 blood concentration samples(96%)was within ± 20%,indicating that the LTG dose prediction model that we established in this study had high accuracy and precision,which could basically meet the needs of clinically formulated individualized drug delivery plans.Conclusion:The pharmacokinetic changes of LTG during pregnancy displayed marked interpatient variation.Gestational stage,the levels of estradiol,estradiol and estriol,ABCB1 rs1128503,ZNF423 rs9940645 gene polymorphism were significant covariates affecting LTG CL/F during pregnancy.The change of estrogen profile during pregnancy was the main reason for the change of LTG CL/F.The RTC values of patients with and without an increased frequency of seizures were significantly different,and increased seizure frequency was associated with a lower RTC.An RTC < 0.62 was a predictor of deteriorating seizures.Therapeutic drug monitoring can support a rational treatment plan for LTG use during pregnancy.We recommend regular monitoring of LTG serum concentrations from prepregnancy to postpartum.