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Influence of the UGT2B7 -161C>T polymorphism on the population pharmacokinetics of lamotrigine in Thai patients

  • Pharmacokinetics and Disposition
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Abstract

Background and objectives:

A high inter-individual variability in the pharmacokinetics of lamotrigine has been observed. Lamotrigine is primarily metabolized by UGT1A4 and UGT2B7, both of which show genetic polymorphisms. Both genetic and non-genetic factors may influence the pharmacokinetics of lamotrigine. The aim of this study was to determine the pharmacokinetic parameters of lamotrigine and to investigate the effect of genetic variants of UGT1A4 and UGT2B7 and various non-genetic factors on its pharmacokinetics.

Methods:

Four single nucleotide polymorphisms (SNPs; UGT1A4 142 T>G, UGT1A4 70C>T, UGT2B7 372A>G, UGT2B7 -161C>T) were identified using the TaqMan Allelic Discrimination Assay. Data were analyzed using NONMEM. Model evaluation was performed using the bootstrap approach and predictive check.

Results:

A total of 116 samples were obtained from 75 patients and included in the population analysis. The use of enzyme inducers, valproic acid, and the UGT2B7-161 C>T SNP were found to significantly influence lamotrigine apparent clearance (CL/F). Lamotrigine CL/F in patients carrying the UGT2B7 -161 CT or TT SNP was 18% lower than that in patients carrying the UGT2B7 -161 CC SNP.

Conclusion:

Both genetic and non-genetic factors were found to influence lamotrigine pharmacokinetics. These factors should be considered when determining lamotrigine dosing. The model presented here could be useful for lamotrigine dose adjustment in clinical practice.

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Acknowledgments

This work was supported by the Thailand Research Fund (MRG-5480122), the 90th Anniversary of Chulalongkorn University Fund (Ratchadaphiseksomphot Endowment Fund), and the Faculty of Pharmacy Research Fund. The authors would like to thank all of the staffs of the epilepsy and psychiatric outpatient clinics, Prasat Neurological Institute. We also thank Dr. Pornanong Aramwit for her invaluable comments and great assistance. We are grateful to all the participants for their contributions to this study.

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Authors and Affiliations

  1. Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand

    Noppaket Singkham & Baralee Punyawudho

  2. Prasat Neurological Institute, Bangkok, Thailand

    Somchai Towanabut & Surang Lertkachatarn

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  1. Noppaket Singkham
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  2. Somchai Towanabut
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  3. Surang Lertkachatarn
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  4. Baralee Punyawudho
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Correspondence to Baralee Punyawudho.

Additional information

Part of this work was presented at the World Conference on Pharmacometrics (WCoP) 2012, Seoul, Korea.

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Singkham, N., Towanabut, S., Lertkachatarn, S. et al. Influence of the UGT2B7 -161C>T polymorphism on the population pharmacokinetics of lamotrigine in Thai patients. Eur J Clin Pharmacol 69, 1285–1291 (2013). https://doi.org/10.1007/s00228-012-1449-5

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  • DOI: https://doi.org/10.1007/s00228-012-1449-5

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