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Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential Implications for Maintenance Dose Optimisation in Future Clinical Trials

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A Letter to the Editor to this article was published on 20 July 2018

A Correction to this article was published on 25 April 2018

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Abstract

Background and Aims

In this study, we evaluate the performance of allometric concepts to predict the implications of age and size on the pharmacokinetics of lamotrigine, and assess the dose rationale across different age groups from 0.2 to 91 years.

Methods

An allometrically scaled pharmacokinetic model was developed using adolescent and adult data, taking into account the effect of comedications. Model parameters were then used to extrapolate lamotrigine pharmacokinetics to older adults (> 65 years), children (4–12 years) and infants and toddlers (0.2–2.0 years). In addition, simulations were performed to identify the implication of different doses and dosing regimens for each population, so as to ensure steady-state concentrations within a predefined reference range.

Results

The pharmacokinetics of lamotrigine was best described using a one-compartment model with first-order absorption and elimination. Carbamazepine, phenytoin, and valproic acid changed systemic clearance (CL) by + 76.5, + 129, and − 47.4%, respectively. Allometric principles allowed accurate extrapolation of disposition parameters to older adults and children older than 4 years of age. A maturation function was required to describe changes in exposure in younger patients. Compared with adults, a child aged 1.7 years has a 31.5% higher CL, after correcting for body weight. Patients > 65 years of age showed a decrease in CL of approximately 15%.

Conclusion

Population pharmacokinetic models are usually limited to a subgroup of patients, which may mask the identification of factors contributing to interindividual variability. The availability of an integrated model including the whole patient population provides insight into the role of age-related changes in the disposition of lamotrigine, and potential implications for maintenance dose optimisation in any future trials.

Trial Registration

According to GlaxoSmithKline’s Clinical Trial Register, data from the GlaxoSmithKline studies LAM100034 and LEP103944, corresponding to ClinicalTrials.gov identifiers NCT00113165 and NCT00264615, used in this work, have been used in previous publications (doi: https://doi.org/10.1212/01.wnl.0000277698.33743.8b, https://doi.org/10.1111/j.1528-1167.2007.01274.x).

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Change history

  • 25 April 2018

    Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential Implications for Dose Optimisation in Epilepsy Patients should read.

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Acknowledgements

The authors thank Khilit Shah for his assistance in retrieving the clinical study data, and Corine Visser for her editorial support.

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Authors and Affiliations

  1. Division of Pharmacology, Leiden Academic Centre for Drug Research, Einsteinweg 55, 2333CC, Leiden, The Netherlands

    Sven C. van Dijkman, Nico C. B. de Jager, Willem M. Rauwé, Meindert Danhof & Oscar Della Pasqua

  2. Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Uxbridge, UB11 1BT, UK

    Oscar Della Pasqua

  3. Clinical Pharmacology and Therapeutics Group, University College London, BMA House (North Entrance), Tavistock Square, London, WC1H 9JP, UK

    Oscar Della Pasqua

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  1. Sven C. van Dijkman
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  2. Nico C. B. de Jager
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  3. Willem M. Rauwé
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Contributions

Sven van Dijkman, Nico de Jager and Willem Rauwé performed the data analysis; Sven van Dijkman and Oscar Della Pasqua wrote the manuscript; and Meindert Danhof and Oscar Della Pasqua coordinated the investigations and reviewed the manuscript.

Corresponding author

Correspondence to Oscar Della Pasqua.

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Conflict of Interest

Sven van Dijkman had support from the Global Research in Paediatrics consortium (GRiP). In addition to his role in GRiP, Oscar Della Pasqua is also Senior Director, Clinical Pharmacology, at GlaxoSmithKline. Nico C. B. de Jager, Willem M. Rauwé and Meindert Danhof declare no conflicts of interest.

Ethical Approval

The research presented in this paper was based on already existing data. The data used were derived from clinical trials performed by GlaxoSmithKline, which were all performed according to the Declaration of Helsinki and any additional ethical and practical standards applicable at the local trial sites.

Funding

The research leading to these results has received funding from the European Union Seventh Framework Programme FP7/2007-2013 under Grant agreement no. 261060.

Additional information

The original version of this article was revised as per the corrections listed in the following: https://doi.org/10.1007/s40262-018-0660-7.

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van Dijkman, S.C., de Jager, N.C.B., Rauwé, W.M. et al. Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential Implications for Maintenance Dose Optimisation in Future Clinical Trials. Clin Pharmacokinet 57, 1039–1053 (2018). https://doi.org/10.1007/s40262-017-0614-5

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