Farmacocinética y farmacodinamia y carbamazepina y sus metabolitos. Cinética poblacional

Resumo

Carbamazepine (CBZ) is a second generation antiepileptic drug extensively used in Neurology and Psyquiatry because of its wide range of action and its efficacy demostrated during years. However, it presents a complex metabolization pathway, the majority of which is metabolized by the 3A4 isoform of cytochrome P450. CBZ is converted to the carbamazepine 10,11-epoxide metabolite (CBZ-E), which also shows anticonvulsivant and antidepressant properties similar to those of the parent compound and contributes significantly to therapeutic benefits of carbamazepine therapy. CBZ-E is metabolized by epoxide hydrolases to 10,11-dihydro –10,11-trans-dihydroxy-CBZ metabolite (CBZ-D), inactive. Given CBZ pharmacokinetic characteristics, including its inductive and autoinductive capacity, its narrow therapeutic range, the presence of an active metabolite and the majority participation of the 3A4 isoform, the risk of CBZ to provoke and suffer clinical pharmacokinetic interactions is high. In addition, the risk of interactions in Neurology and Psyquiatry is higher since the diseases being treated require long-term treatments and polytherapy. Similar to many antiepileptic drugs, Therapeutic Drug Monitoring (TDM) of CBZ is routinely used to optimize dosing. The carbamazepine 10,11-epoxide concentration is not usually measured or considered in routine TDM. ON the other hand, Carbamazepine TDM is commonly performed using commercially available immunoassays. Many different methods have been used for the estimation of CBZ, but not of their metabolites, which requires the use of reference techniques such as High Performance Liquid Chromatography (HPLC). The main aim of this study was to analyze the influence of certain demographic or anthropometric variables and comedication on pharmacokinetics of CBZ and their metabolites, and the pharmacokinetics parameters. The secondary aim was to determine the relation between the effectiveness and toxicity of this drug and the serum concentrations of CBZ and its metabolites. In addition, the concordance between both analitic techniques and mathematical equations to estimate CBZ-E levels from serum concentrations of CBZ were also described. An observational single-center retrospective study of adult patients receiving oral CBZ pharmacokinetics subject to monitoring from January 2010 to December 2019 was conducted. Serum samples from patients were analysed by HPLC and by Fluorescence Polarization Immunoassay. The elimination half life and estimated clearance of CBZ are influenzed by sex and weight. Sex is a conditioning factor in elimination half life, that is significantly longer in men, due to the higher volumen of distribution. Weight remarkably affects the apparent volume of distribution, showing a progressive increase with the weight gain. The variables which showed a greater influence on the serum concentrations of CBZ-E were the daily dose normalized by dose weight, age and valproic acid intake. Regarding to toxicity, the involved variables were age and the CBZ-E/CBZ ratio. A high correlation was observed between CBZ levels mesured by autoanalyzer and by HPLC, with a concordance of 0.94. The results in our research make advisable to undertake therapeutic drug monitoring of CBZ-E and CBZ-D pharmacokinetics. The determination only of the serum concentrations of the CBZ could mask the alteration of the epoxide levels, which are related to efficacy and toxic effects. The TDM of the metabolites of CBZ, epoxide and diol, helps to identify and describe interactions that would otherwise remain unexplained. Knowing the mechanism of the interaction allows adjusting the dosage and guiding clinicians in the management of the interaction.