European Journal of Clinical Pharmacology

, Volume 74, Issue 5, pp 583–591 | Cite as

Population pharmacokinetics of lamotrigine co-administered with valproic acid in Chinese epileptic children using nonlinear mixed effects modeling

  • Shansen Xu
  • Limin Liu
  • Yanan Chen
  • Mei Liu
  • Tong Lu
  • Huanxin Wang
  • Shihao Liu
  • Mingming Zhao
  • Limei Zhao
Pharmacokinetics and Disposition



The aims of this study were to develop a population pharmacokinetic (PPK) model of lamotrigine (LTG) in Chinese epileptic children by using nonlinear mixed effects modeling (NONMEM) and to investigate the effects of valproic acid (VPA) and genetic polymorphisms of the major metabolizing enzymes (UGT1A4, UGT2B7) on the pharmacokinetics of LTG.


A total of 182 epileptic children who were treated with LTG as monotherapy or as part of combination therapy were included in this study as the model group, and 61 patients were included as the validation group. The steady-state serum trough concentrations of LTG and VPA were determined using a high-performance liquid chromatography method and fluorescence polarization immunoassay, respectively. Patients were genotyped for three single nucleotide polymorphisms (UGT1A4 142T>G, UGT2B7 −161C>T, and UGT2B7 802C>T). PPK analysis was performed with NONMEM using first-order absorption and elimination. Bootstrap, normalized prediction distribution errors and external evaluations were performed to determine the stability and predictive performance of the model.


For the final model, the oral clearance (CL/F) of LTG was estimated to be 0.705 L/h with inter-individual variability (IIV) of 21.3%. The estimates generated by NONMEM indicated that the LTG CL/F was significantly influenced by patient body weight (increased with an exponent of 0.574) and VPA concentration (decreased with linearity of 0.273 with co-administration). However, no significant effects of UGT1A4 or UGT2B7 polymorphisms on LTG CL/F were noted in this population of Chinese children.


This study confirms the interaction of LTG with VPA, which likely depends on VPA concentration. The LTG PPK model developed in this study could be useful for individualizing LTG dosage regimens in pediatric patients receiving combination therapy, especially therapy that includes VPA.


Population pharmacokinetics Lamotrigine Valproic acid UGT polymorphisms Chinese children 



The authors would like to thank Professor Zheng Jiao from Huashan Hospital, Fudan University, China, for his invaluable advice and support. This project was supported by grants from the National Natural Science Foundation of China (No. 81673510 and 81703628).

Compliance with ethical standards

All patients’ guardians were informed about the purpose of the study, and the Shengjing Hospital ethics committee approved the study.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

228_2018_2414_Fig3_ESM.gif (12 kb)
Figure S1

A plot of lamotrigine concentration (μg/mL) versus time after dose (h). (GIF 12 kb)

228_2018_2414_MOESM1_ESM.tiff (894 kb)
High resolution image (TIFF 894 kb)
228_2018_2414_Fig4_ESM.gif (134 kb)
Figure S2

Effects of UGT1A4 142 T > G, UGT2B7–161C > T, and UGT2B7 802C > T polymorphisms on lamotrigine oral clearance (CL/F). (GIF 133 kb)

228_2018_2414_MOESM2_ESM.tif (62.3 mb)
High resolution image (TIFF 63836 kb)
228_2018_2414_Fig5_ESM.gif (76 kb)
Figure S3

Normalized prediction distribution error (NPDE) analysis of the final model: (A) quantile-quantile plot of the NPDE versus the expected standard normal distribution; (B) histogram of the NPDE with the density of the standard normal distribution overlaid; (C) scatter plot of NPDE versus time after dose (TAD); and (D) scatter plot of NPDE versus population prediction. (GIF 75 kb)

228_2018_2414_MOESM3_ESM.tif (12.7 mb)
High resolution image (TIFF 12956 kb)
228_2018_2414_Fig6_ESM.gif (47 kb)
Figure S4

Goodness-of-fit plots of the final model for the validation group: (A) observed versus individual predicted concentrations; (B) observed versus population predicted concentrations; (C) conditional weighted residuals (CWRES) versus population predicted concentrations; and (D) CWRES versus time after dose. The red lines in the upper and lower panels represent loess smooth lines and linear fit lines, respectively. (GIF 46 kb)

228_2018_2414_MOESM4_ESM.tif (554 kb)
High resolution image (TIFF 554 kb)
228_2018_2414_MOESM5_ESM.docx (18 kb)
Table S1 Results of hypothesis testing in the model development process (DOCX 17 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Shansen Xu
    • 1
  • Limin Liu
    • 1
  • Yanan Chen
    • 1
  • Mei Liu
    • 1
  • Tong Lu
    • 1
  • Huanxin Wang
    • 1
  • Shihao Liu
    • 1
  • Mingming Zhao
    • 1
  • Limei Zhao
    • 1
  1. 1.Department of PharmacyShengjing Hospital of China Medical UniversityShenyangPeople’s Republic of China

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