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Population Pharmacokinetics of Levetiracetam: A Systematic Review

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Abstract

Background

Levetiracetam has been widely used as a treatment option for different types of epilepsy in both adults and children. Because of its large between-subject variability, several population pharmacokinetic studies have been performed to identify its pharmacokinetic covariates, and thus facilitate individualised therapy.

Objective

The aim of this review was to provide a synopsis for population pharmacokinetic studies of levetiracetam and explore the identified influencing covariates.

Methods

We systematically searched the PubMed and Embase databases from inception to 30 June 2020. The information on study designs, target population, model characteristics, and identified covariates was summarised. Moreover, the pharmacokinetic profiles were compared among neonates, children, and adults.

Results

Fourteen studies were included, among which two involved neonates, four involved children, two involved both children and adults, and six involved adults only. The median value of apparent clearance for children (0.074 L/h/kg [range 0.038–0.079]) was higher than that for adults (0.054 L/h/kg [range 0.039–0.061]). Body weight was found to significantly influence the apparent clearance and volume of distribution, whereas renal function influenced the clearance. Likewise, coadministration with enzyme-inducing antiepileptic drugs (such as carbamazepine and phenytoin) increased the drug clearance by 9–22%, whereas coadministration with valproate acid decreased it by 18.8%.

Conclusion

Levetiracetam dose regimen is dependent on the body size and renal function of patients. Further studies are needed to evaluate levetiracetam pharmacokinetics in neonates and pregnant women.

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Acknowledgements

The authors would like to sincerely thank Dr. Silvia Romano Moreno from Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, San Luis Potosí, México; Dr. V. Lima-Rogel from the Neonatal Intensive Care Unit, Hospital Central ‘Dr. Ignacio Morones Prieto’, San Luis Potosí, México; Dr. Yun Seob Jung from the Department of Pharmacology, Yonsei University College of Medicine, Korea; and Dr. Brigitte Lacroix from UCB Pharma SA, Belgium, for providing details about the research and active discussions on the coding. The authors would also like to thank Hai-ni Wen, MPharm, and Yi-wei Yin, PharmD, from Shanghai Chest Hospital, and PhD candidate Xiao-qin Liu from Fudan University for their critical comments. Finally, the authors would like to thank Editage (http://www.editage.cn) for English-language editing.

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Correspondence to Zheng Jiao.

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Funding

Professor Zheng Jiao is supported by the Key Innovative Team of Shanghai Top-Level University Capacity Building in Clinical Pharmacy and Regulatory Science at Shanghai Medical College, Fudan University (HJW-R-2019-66-19).

Conflict of interest

Zi-ran Li, Chen-yu Wang, Xiao Zhu, and Zheng Jiao declare they have no conflicts of interest.

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Author contributions

ZL, CW, and ZJ designed the review and planned the work that led to the manuscript. ZL and CW performed the literature search and data analysis. ZL, XZ, and ZJ drafted and revised the manuscript. All authors approved the final version of this manuscript.

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Fig. S1 Investigated and identified covariates for clearance of LEV. AST: aspartate aminotransferase; ALT: alanine aminotransferase; BMI: body mass index; BSA: body surface area; eGFR: the estimated glomerular filtration rate; Inducer: enzyme-inducing antiepileptic drugs (PDF 136 KB)

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Li, Zr., Wang, Cy., Zhu, X. et al. Population Pharmacokinetics of Levetiracetam: A Systematic Review. Clin Pharmacokinet 60, 305–318 (2021). https://doi.org/10.1007/s40262-020-00963-2

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