Research Article |
Corresponding author: Angel T. Alvarado ( eaa.alvarado@hotmail.com ) Academic editor: Georgi Momekov
© 2022 Angel T. Alvarado, Gustavo Paredes, Gregoriana García, Alexis Morales, Ana María Muñoz, María Saravia, Ricardo Losno, María R. Bendezú, Haydee Chávez, Jorge A. García, Mario Pineda, Luis Sullón-Dextre.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation:
Alvarado AT, Paredes G, García G, Morales A, Muñoz AM, Saravia M, Losno R, Bendezú MR, Chávez H, García JA, Pineda M, Sullón-Dextre L (2022) Serum monitoring of carbamazepine in patients with epilepsy and clinical implications. Pharmacia 69(2): 401-406. https://doi.org/10.3897/pharmacia.69.e82425
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Carbamazepine is a drug with a narrow therapeutic range that requires clinical monitoring, since its toxic effects are not easily predictable, and the therapeutic level can vary. Our study aimed to monitor the serum level and determine the concentration/dose relationship of carbamazepine in people with epilepsy, analyzing its clinical implication. It is observed that 90.48% of the study volunteers present serum level values (4.3–10.4 mg/L) within the therapeutic range (4–12 mg/L); 7.14% present supratherapeutic levels (12.7–14.4 mg/L), 2.38% subtherapeutic (0.93 mg/L). The findings indicate a negative correlation (r = -0.616; r2 = 0.379; p = 0.001), between the dose (mg/day) and the dose ratio (mg/L/mg/day); and a positive correlation (r = 0.544; r2 = 0.296; p = 0.002), between the dose (mg/day)-serum concentration (mg/L). ANOVA and Tukey’s test mean difference is significant (p<0.05). It is concluded that there is a positive and significant linear correlation between daily doses and serum carbamazepine concentrations, which should be considered to individualize the dose and optimize clinical results.
Carbamazepine, Level/dose, Serum monitoring, Personalized dose, Therapeutic range
Precision medicine is especially applied to chronic diseases such as epilepsy, which is based on the association genotype-metabolic phenotype and drug, serum level/dose, ethnicity, miscegenation, and sex, to prescribe the antiepileptic drug (AED), with the precise dose from the start of pharmacological treatment, to minimize side effects and optimize pharmacological therapy (
Chronic use of carbamazepine can induce its own metabolism, induce UGT2B7, epoxide hydrolase, CYP3A4 (
For these considerations, therapeutic drug monitoring (TDM) at the hospital level should be a routine clinical practice, to measure serum concentration, determine the level/dose ratio (N/D), identify possible drug interactions and side effects, which in many cases are the factors of therapeutic failure (
The PubMed-Medline database on studies of level/dose (N/D) and therapeutic monitoring of drugs has been reviewed, being limited these investigations in patients with epilepsy in Venezuela, for which it is worth carrying out them and mainly of drugs with a narrow margin therapeutic, generating scientific evidence so that these studies are a routine clinical practice in the Neurology Services of the National Hospitals and in the Clinics. The objective of the present study was to monitor the serum level and determine the concentration/dose relationship of carbamazepine in people with epilepsy, analyzing its clinical implication.
Descriptive, cross-sectional, non-probabilistic sampling study with prospective recruitment from January 2019 to December 2021 (
A single blood sample was obtained from each patient attending the Neurology Service for their routine medical control. These samples were stored refrigerated at -21 °C until analysis (
Patients who received CBZ monotherapy for 4 weeks (time in which the drug will be in its steady-state), do not consume medications that are not prescribed by the doctor of the Neurology Service, comply with the dose and frequency of administration of the medication, at the examination doctor, not manifest liver or kidney dysfunction and give their consent in writing (
Sample extractions were performed before the next scheduled dose and no less than 10 h after the last dose of CBZ (
3 mL of venous blood was extracted in Vacutainer tubes, BD Bioscience, for the quantification of the drug in the serum, the samples were centrifuged within two hours of sampling at 8000 rpm for 10 minutes. Clear supernatant was taken from the serum fractions and stored at -21 °C until analysis. Then, 0.5 mL of each serum sample was measured, without any special treatment is necessary, determining total carbamazepine in the serum by the CEDIA method (Cloned Donor Enzyme Immunoassay) on the Indiko Thermo Fisher Scientific equipment (Waltham, Massachusetts, USES).
The study was developed in strict compliance with national and international ethical standards, in the Belmont Report, Declaration of Helsinki with the current revision. The Institutional Medical Board approved this study as a minimal risk investigation, for using blood samples from routine clinical practice, through certificate 002-JMI-2019. Each volunteer who signed the Informed Consent was assigned a code to guarantee confidentiality and anonymity.
The data obtained were analyzed by one-way analysis of variance (ANOVA) followed by Tukey’s test as post-hoc analysis. A value of p<0.05 was considered statistically significant. Pearson’s correlation coefficient was also calculated to establish the relationship between carbamazepine level and dose. The Statistical Software GraphPad Prism 9 was used. Version 9.1.2.
Of a total of 100 patients informed about the study, 42 met the selection criteria. Table
Statistic | Dose (mg/day) | Cp (mg/L) | Age (years) | Sex | |
---|---|---|---|---|---|
Male n (%) | Female n (%) | ||||
Mean | 730.95 | 7.67 | 36.26 | 25(59.52%) | 17(40.48%) |
SD | 356.47 | 2.52 | 11.59 | ||
Range | 300–1600 | 0.93–14.4 | 19–62 |
Table
Therapeutic, subtherapeutic and supratherapeutic level of carbamazepine.
Statistic | Therapeutic level (4-12 mg/L) | Subtherapeutic (<4 mg/L) | Supratherapeutic (>12 mg/L) | Dose ratio range (mg.L/mg.day) |
---|---|---|---|---|
n(%) | 38 (90.48%) | 1 (2.38%) | 3 (7.14%) | |
Mean | 7.39 | 0.93 | 13.37 | 0.78 |
SD | 1.75 | 0.91 | 0.29 | |
Range | 4.3–10.4 | 12.7–14.4 | 0.30–1.64 |
Fig.
The relationship of the dose (mg/day)-serum concentration (mg/L) and the therapeutic range is shown in Fig.
In the present study, the serum concentration level was determined with a single sampling point, observing that the range of the serum concentration level is 4.3–10.4 mg/L, in 90.48% (38/42) of the patients. These values are above the minimum effective serum concentration (CmE 4 mg/L) and below the maximum effective serum concentration (CME 12 mg/L) (
Regarding the correlation, a negative or inverse correlation was observed in the level/dose ratio (mg.L/mg.day) between the dose (mg/day); and a positive and statistically significant linear correlation between the daily doses administered (mg/day) and serum concentrations (mg/L). Our findings are based on and contrasted with several previously published studies.
In the case of the group of patients with subtherapeutic and supratherapeutic levels, they require routine clinical monitoring, and based on the N/D index, adjust the dose, to propose the correct dose and at the correct time (
Our results must be considered in the context of several limitations. First, the sample size was not calculated from patients with a diagnosis of epilepsy (n = 42), so it is not representative of the population that attends the Neurology Service, its selection was for convenience and prospective. Second, the use of the CEDIA method that is available in our hospitals; both limitations are being considered for incorporation in future studies by our research group, to obtain a more robust statistical relationship, using the high-resolution chromatographic method to obtain serum levels with greater precision. Notwithstanding the foregoing, this study shows a significant correlation between dose/serum level. At the same time, it is recommended to incorporate pharmacogenetic studies that allow detecting poor metabolizer patients, to avoid overdose and toxicity of carbamazepine and other antiepileptic drugs (
It is concluded that there is a positive and significant linear correlation between the daily doses and the concentrations of carbamazepine in serum, which should be considered to individualize the dose and optimize the clinical result. TDM should be a routine clinical practice in our hospitals for the management of patients with epilepsy, minimizing side effects, and avoiding therapeutic failure.
Society of Molecular Pharmacology of Peru, and Latin American Society of Pharmacogenomics and Personalized Medicine.