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A Physiologically Based Pharmacokinetic Model for Optimally Profiling Lamotrigine Disposition and Drug–Drug Interactions

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objectives

Lamotrigine (Lamictal®) is a broad-spectrum antiepileptic drug available in both immediate-(IR) and extended-release (XR) formulations. Here, we present a new physiologically based pharmacokinetic (PBPK) model for IR and XR formulations of lamotrigine to predict disposition in adults and children, plus drug–drug interactions (DDIs).

Methods

Models for lamotrigine IR and XR formulations were constructed using a Simcyp® Simulator. Concentration–time profiles were simulated for lamotrigine IR single (SD) and steady-state (SS) doses ranging from 25 to 200 mg in adults, as well as 2 mg/kg (SD), and 7.7–9.4 mg/kg (SS) in children aged between 4 and 17 years. Lamotrigine XR profiles were simulated for SD and SS doses ranging from 250 to 400 mg. DDI prediction with lamotrigine was simulated in adults with enzyme-inducing drugs, rifampin (rifampicin) and ritonavir, as well as the enzyme inhibitor, valproic acid.

Results

The lamotrigine model predicted adult area-under-the-curve (AUC) and peak plasma concentration (Cmax) results for IR SD within 35% of observed data; lamotrigine IR SS dosing was within 10% and 30% of observed data, respectively. Pediatric lamotrigine IR SD AUC and Cmax values were within 10% and 15% of observed data, respectively. AUC and Cmax values for lamotrigine XR SD simulated in adults were within 20% of observed data; similarly lamotrigine XR SS parameters were within 10%. Concerning DDI simulation in adults, predicted-to-observed lamotrigine AUC ratios [AUCDDI/AUCalone] were within 15% for ritonavir and rifampin, and 20% for valproic acid.

Conclusions

Our developed PBPK lamotrigine profile accurately predicts DDIs and lamotrigine IR/XR formulation disposition in adults and children. This PBPK model will be helpful in designing future DDI studies for co-administration of lamotrigine with other drugs and in designing individualized patient dosing regimens.

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Acknowledgements

Simcyp Limited., a Certara Company, is gratefully acknowledged for an academic license for the Simcyp® population-based simulator and for providing user support.

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  1. School of Pharmacy, Husson University, 1 College Circle, Bangor, ME, 04401, USA

    Todd M. Conner & Tao Zhang

  2. School of Pharmacy, West Virginia University, 1124 Health Science Center North, Morgantown, WV, 26506, USA

    Ronald C. Reed

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This work was sponsored by the Husson University Research Grant.

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Conner, T.M., Reed, R.C. & Zhang, T. A Physiologically Based Pharmacokinetic Model for Optimally Profiling Lamotrigine Disposition and Drug–Drug Interactions. Eur J Drug Metab Pharmacokinet 44, 389–408 (2019). https://doi.org/10.1007/s13318-018-0532-4

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