Empirical medication difficult to reach medication level - CBZ
发布日期：
2023-12-19
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Carbamazepine is still used as a first-line drug in clinical practice


Carbamazepine (CBZ) is one of the classic anti-epileptic drugs (AEDs), which was introduced in the 1960s and 1970s. As the first-line drug of choice (DOC), it still plays a leading role in the treatment of epilepsy, especially for different focal epilepsy syndromes [2]. In addition, this drug is used to treat idiopathic neuralgia of the trigeminal and glossopharyngeal nerves and pain caused by diabetic neuropathy. Carbamazepine can block voltage-gated sodium channels, thereby stabilizing the cell membrane of nerve fibers, inhibiting neuronal discharge, and reducing excitatory synaptic transmission.

Currently, carbamazepine alone is the main therapy in patients with epilepsy [3]. The dosage for epilepsy in adults is 0.8-1.2 g/day 2-3 times a day, and in children 1 to 15 years old, the dosage is 0.1-1 g/day (10-25 mg/kg/day). However, CBZ is a drug that has strong effects on metabolic processes and may cause clinically significant drug interactions. CBZ not only reduces the concentration of other drugs taken together by inducing isoenzymes such as CYP3A4 and CYP1A2, but also affects its own blood drug concentration during the interaction with these isoenzymes [4]. The patient's blood drug concentration is difficult to control after taking the drug.   


Empirical medication difficult to reach medication level - CBZ



Experimental research results

In order to analyze the actual drug concentration in patients during empirical medication, the Department of Pharmacology and Therapeutics of the Kuyavian-Pomeranian Province conducted a retrospective analysis of CBZ levels in patients in the province from 1991 to 2011. The survey analyzed 710 outpatient and inpatient patients. The average age of the study subjects was 19 years old, the average height was 168 cm, the average weight was 59 kg, and the average body mass index (BMI) was 22.49 kg/m2. The most common reason for hospitalization was epilepsy - 94.6%. The average daily carbamazepine intake of the patients tested was 600 mg (oral tablets). 3.1% of the cases took it only once, 66.1% of the cases took it twice a day, and 26.9% of the cases took it at least three times a day. Although the mean concentration of carbamazepine in the serum of the study population was 5.58 μg/ml, which was within the therapeutic range, 29% of the patients were not within the therapeutic range.


Empirical medication difficult to reach medication level - CBZ

Possible associated factors of carbamazepine blood concentration

CBZ

In order to explore which factors may lead to deviations in blood drug concentrations, the study analyzed the influence levels of factors such as reasons for hospitalization, gender, age, weight, and dosage.

First, there were statistically significant differences in carbamazepine concentrations depending on the reasons for hospitalization. This may be due to the different levels of medication taken by patients with different reasons for hospitalization. For example, the average concentration of patients with suicidal tendencies was 21.0 μg/ml, which was significantly higher than the level of 5.52 μg/ml in patients with epilepsy, and the median drug concentration of patients with overdose also reached 7.24 μg/ml. Secondly, body weight is an important factor to consider. On average, patients with subtherapeutic CBZ concentrations received a daily dose of 9.92 mg per kilogram of body weight; patients with therapeutic levels, a daily dose of 12.86 mg; and patients with above-therapeutic concentrations, a daily dose of 12.50 mg.

Furthermore, the age factor was found to be significantly related to the difference in CBZ concentration (divided into 3-17 years old and over 18 years old). The concentration of the group ≥18 years old was lower, which may come from the lower concentration of the group ≥18 years old. The risk of not following medical advice is higher. Another influence of age is that although the dosage per kilogram of body weight for people aged 3-17 years is significantly higher than that of people over 18 years old, this may be due to the higher activity of their CYP3A4 isoenzyme and the faster metabolism of CBZ, which exceeds the therapeutic level. The situation is less. In a consideration of gender factors, pregnancy can also affect CBZ concentrations, as increased metabolism reduces its concentration.

Based on the above complex factors, from a clinical pharmacology perspective, TDM should become a standard procedure for CBZ, just as TDM is currently used in digoxin treatment.



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Empirical medication difficult to reach medication level - CBZ



References

1.Grzesk, G., et al., Therapeutic Drug Monitoring of Carbamazepine: A 20-Year Observational Study. J Clin Med, 2021. 10(22).
2.Fisher, R.S., et al., Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia, 2017. 58(4): p. 522-530.
3.Nadkarni, S., J. LaJoie, and O. Devinsky, Current treatments of epilepsy. Neurology, 2005. 64(12 Suppl 3): p. S2-11.
4.Fuhr, L.M., et al., Pharmacokinetics of the CYP3A4 and CYP2B6 Inducer Carbamazepine and Its Drug-Drug Interaction Potential: A Physiologically Based Pharmacokinetic Modeling Approach. Pharmaceutics, 2021. 13(2).




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