Population toxicokinetics of carbamazepine and its metabolite carbamazepine-10,11-epoxide in adults

ABSTRACT

Background

Carbamazepine is one of the most commonly used antiseizure medications. Although carbamazepine pharmacokinetics in epileptic patients is well described, much less is known about these processes in the patients who experienced self-poisoning episode by this drug. Therefore, the aim of our investigation was to perform population toxicokinetics of carbamazepine and its metabolite carbamazepine-10,11-epoxide in adults.

Research design and methods

Software program NONMEM and the ADVAN2 TRANS2 subroutine were used for establishing a population toxicokinetic model for the estimation of clearance and volume of distribution based on of the sum values of carbamazepine and carbamazepine-10,11-epoxide concentrations.

Results

Our results indicated that the adult patients’ ability to eliminate carbamazepine and carbamazepine-10,11-epoxide following acute carbamazepine self-poisoning was strongly associated with the high levels of CRP and ASP, as well as by the treatment with sedation.

Conclusions

Our study should provide better understanding of the toxicokinetics of carbamazepine taken in overdose and better management of patient population admitted to hospital.

KEYWORDS:

• Adult population
• Carbamazepine
• Carbamazepine-10
• 11-epoxide
• NONMEM
• Poisoning
• Population toxicokinetics

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Conflict of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author Contributions

V Lukic, V Dragojevic-Simić, and S Jankovic jointly designed the study and defined research questions; V Lukic and N Petrovic did most of the purification of the files for missing data and artifacts, and statistical analysis; V Lukic, S Jankovic and N Petrovic performed population toxicokinetic analysis; S Djordjevic performed liquid chromatography drug analysis; V Lukic, V Dragojevic-Simić, and S Jankovic contributed to the tables and figures creation and interpretation of data;, V Dragojevic-Simić, V Lukic and S Jankovic drafted the working version of the manuscript but S Vucinic, J Jovic Stosic and S Djordjevic contributed to the final version of the text and had important intellectual contributions. Authors have agreed on the journal to which the article will be submitted. They reviewed and agreed on all versions of the articles before submission, during revision, the final version accepted for publication, and any significant changes introduced at the proofing stage. They agree to take responsibility and be accountable for the contents of the articles and to share responsibility to resolve any questions raised about the accuracy or integrity of the published work.

Additional information

Funding

This manuscript was funded by the Medical Faculty of the Military Medical Academy, University of Defence, 11000 Belgrade, Serbia (Grant No. MFVMA/08/22-24).