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Pharmacometabolomics applied to zonisamide pharmacokinetic parameter prediction

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Abstract

Introduction

Zonisamide is a new-generation anticonvulsant antiepileptic drug metabolized primarily in the liver, with subsequent elimination via the renal route.

Objectives

Our objective was to evaluate the utility of pharmacometabolomics in the detection of zonisamide metabolites that could be related to its disposition and therefore, to its efficacy and toxicity.

Methods

This study was nested to a bioequivalence clinical trial with 28 healthy volunteers. Each participant received a single dose of zonisamide on two separate occasions (period 1 and period 2), with a washout period between them. Blood samples of zonisamide were obtained from all patients at baseline for each period, before volunteers were administered any medication, for metabolomics analysis.

Results

After a Lasso regression was applied, age, height, branched-chain amino acids, steroids, triacylglycerols, diacyl glycerophosphoethanolamine, glycerophospholipids susceptible to methylation, phosphatidylcholines with 20:4 FA (arachidonic acid) and cholesterol ester and lysophosphatidylcholine were obtained in both periods.

Conclusion

To our knowledge, this is the only research study to date that has attempted to link basal metabolomic status with pharmacokinetic parameters of zonisamide.

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  • 14 June 2018

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Acknowledgements

The authors would like to thank Dr. Jennifer Kirwan for her valuable comments to the manuscript. Also to the scientific committee and the participants of MOVISS 2017 Bio&Data, Vorau, Austria, for their feedback in metabolomics and interest in our data.

Funding

The ZNS bioequivalence study was funded by Laboratorios Normon, Ronda de Valdecarrizo 6, 28760 Tres Cantos, Madrid, SPAIN. The research project has been cofinanced by the Ministerio de Economia y Competitividad within the INNPACTO program (IPT-2012-0576-090000) and by the European Regional Development Fund (ERDF “A way of making Europe”).

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Authors and Affiliations

  1. Clinical Pharmacology Department, La Paz University Hospital, School of Medicine, IdiPAZ, Autonomous University of Madrid, Madrid, Spain

    J. C. Martínez-Ávila, A. García Bartolomé, I. García, Hoi Y. Tong, L. Díaz, P. Guerra, J. Frías, A. J. Carcás Sansuan & A. M. Borobia

  2. Medical and Molecular Genetics Institute (INGEMM), La Paz University Hospital, Rare Diseases Networking Biomedical Research Center (CIBERER), ISCIII, Madrid, Spain

    I. Dapía

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  1. J. C. Martínez-Ávila
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  2. A. García Bartolomé
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Contributions

JCM-A and AJCS and AMB designed the study. JF, PG, HYT provided the pharmacokinetics study. AGB, IG, ID and LD contributed with the metabolomics results interpretation. JCM-A, AGB and AMB, wrote the manuscript. JCM-A perform the statistical analysis. All authors revised and approved the final version of the manuscript.

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Correspondence to J. C. Martínez-Ávila or A. J. Carcás Sansuan.

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Martínez-Ávila, J.C., García Bartolomé, A., García, I. et al. Pharmacometabolomics applied to zonisamide pharmacokinetic parameter prediction. Metabolomics 14, 70 (2018). https://doi.org/10.1007/s11306-018-1365-5

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