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Nonlinear mixed effects modelling approach in investigating phenobarbital pharmacokinetic interactions in epileptic patients

  • Pharmacokinetics and Disposition
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Abstract

Purpose

The present study aimed to establish population pharmacokinetic model for phenobarbital (PB), examining and quantifying the magnitude of PB interactions with other antiepileptic drugs concomitantly used and to demonstrate its use for individualization of PB dosing regimen in adult epileptic patients.

Methods

In total 205 PB concentrations were obtained during routine clinical monitoring of 136 adult epilepsy patients. PB steady state concentrations were measured by homogeneous enzyme immunoassay. Nonlinear mixed effects modelling (NONMEM) was applied for data analyses and evaluation of the final model.

Results

According to the final population model, significant determinant of apparent PB clearance (CL/F) was daily dose of concomitantly given valproic acid (VPA). Typical value of PB CL/F for final model was estimated at 0.314 l/h. Based on the final model, co-therapy with usual VPA dose of 1000 mg/day, resulted in PB CL/F average decrease of about 25 %, while 2000 mg/day leads to an average 50 % decrease in PB CL/F.

Conclusions

Developed population PB model may be used in estimating individual CL/F for adult epileptic patients and could be applied for individualizing dosing regimen taking into account dose-dependent effect of concomitantly given VPA.

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Acknowledgments

This work was conducted as a part of the project Experimental and Clinical Pharmacological Investigations of Mechanisms of Drug Action and Interactions in Nervous and Cardiovascular System (No. 175023) funded by the Ministry of Education, Science and Technological Development, Belgrade, Republic of Serbia. We would like to acknowledge Prof. Milena Pokrajac for her significant contribution to the research. We are very grateful to the personnel from the Institute of Mental Health, Belgrade. Additionally, the authors would like to express great appreciation to our colleague Spec Clin Pharm Ružica Veličković for her valuable role in collecting the data.

Conflict of interest

None.

Author Contributions

Ž.M., B.M., M.P. designed the study. B.M., Ž.M. and K.V. performed the trial. K.V. gathered the data. K.V., M.J. and B.G. performed the analysis. B.M., K.V., S.V.K., B.G. and M.J. interpreted the results and wrote the manuscript.

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Authors and Affiliations

  1. Department of Pharmacokinetics and Clinical Pharmacy, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, Belgrade, 11000, Serbia

    Katarina Vučićević, Marija Jovanović, Bojana Golubović, Sandra Vezmar Kovačević & Branislava Miljković

  2. Institute of Mental Health, Department of Epilepsy and Clinical Neurophysiology, School of Medicine, University of Belgrade, Belgrade, Serbia

    Žarko Martinović

  3. Department of Pharmacology, Clinical Pharmacology and Toxicology, School of Medicine, University of Belgrade, Belgrade, Serbia

    Milica Prostran

Authors
  1. Katarina Vučićević
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  2. Marija Jovanović
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  3. Bojana Golubović
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  4. Sandra Vezmar Kovačević
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  5. Branislava Miljković
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  6. Žarko Martinović
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  7. Milica Prostran
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Corresponding author

Correspondence to Katarina Vučićević.

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Vučićević, K., Jovanović, M., Golubović, B. et al. Nonlinear mixed effects modelling approach in investigating phenobarbital pharmacokinetic interactions in epileptic patients. Eur J Clin Pharmacol 71, 183–190 (2015). https://doi.org/10.1007/s00228-014-1778-7

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  • DOI: https://doi.org/10.1007/s00228-014-1778-7

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