Klinická farmakologie a farmacie – 2/2021

KLINICKÁ FARMAKOLOGIE A FARMACIE / Klin Farmakol Farm 2021; 35(2): 49–53 / www.klinickafarmakologie.cz 50 PŮVODNÍ PRÁCE THE EFFECT OF VALPROIC ACID ON PLASMA LEVEL OF CARBAMAZEPINE AND CARBAMAZEPINE-10, 11-EPOXIDE IN LONG-TERM TREATMENT WITH SLOW-RELEASE DRUG FORMULATIONS IN PEDIATRIC PATIENTS; THE IMPORTANCE OF TDM Výsledky (uvedeny jako průměr ± směrodatná odchylka): Ačkoliv pacienti léčení CBZ + VPA užívali vyšší dávky než pacienti na monoterapii: PDD 557 ± 204 vs. 400 ± 187mg, p <0.001; DBW 20.2 ± 10.5 vs. 13.5 ± 5.8mg/kg, p <0.001, nebyl zaznamenán rozdíl v průměrné koncentraci CBZ (5.1 ± 1.4 vs. 5.3 ± 1.9mg/l), CBZ-E (1.2 ± 0.8 vs. 1.1 ± 0.9mg/l), poměru CBZ-E/CBZ (0.24 ± 0.12 vs. 0.22 ± 0.19) ani v rozložení koncentrací podle terapeutického rozmezí. V terapeutickémoptimu bylo 86%vs. 77% koncentrací. Koncentrace nad horní hranicí terapeutického rozmezí se nevyskytovaly. U CBZ + VPA byly nižší poměry koncentrace CBZ/PDD: 10.3 × 10 -3 ± 4.2 × 10 -3 , vs. 14.9 × 10 -3 ± 6.4 × 10 -3 mg × L -1 /mg, p <0.001; CBZ/DBW: 0.31 ± 0.17, vs. 0.44 ± 0.19 mg × l -1 /mg × kg -1 , p < 0.001. Obdobně u 11 pacientů, kteří byli vlastní kontrolou: poměr koncentrace CBZ/PDD 10.9 × 10 -3 ± 3.7 × 10 -3 vs. 15.0 × 10 -3 ± 5.7 × 10 -3 , p < 0.01; CBZ/DBW 0.35 ± 0.10 vs. 0.40 ± 0.14, p <0.05. Zdá se, že VPAmá indukční efekt nametabolismus CBZ. Na dávce závislé nežádoucí účinky (ataxie, bolest hlavy) byly popsány u 4 pacientů na monoterapii. Koncentrace CBZ a CBZ-E se nelišila od pacientů bez NÚL, byl však vyšší poměr CBZ-E/CBZ 6.8 × 10 -3 ± 1.6 × 10 -3 vs. 3.1 × 10 -3 ± 3.6 × 10 -3 , a CBZ-E/PDD 0.32 ± 0.06 vs. 0.21 ± 0.20, p < 0.05. Závěr: Významná interakce mezi CBZ a VPA byla úspěšně eliminována úpravou dávkování pomocí TDM. Klíčová slova: karbamazepin, karbamazepin-epoxid, kyselina valproová, interakce, léčivé přípravky s pomalým uvolňováním. Introduction Carbamazepine (CBZ) and valproic acid (VPA) are the drugs of choice in the treatment of epilepsy. Their concomitant administration is quite common (1–3). CBZ is extensively metabolized in the liver, primarily by CYP 3A4, to active carba- mazepine-10,11-epoxide (CBZ-E) (4, 5) whe- reas CYP2C8 is a minor pathway (5). CBZ-E is further metabolized by epoxide-hydrolase to inactive 10,11-dihydro-carbamazepine (carbamazepine-diol), which is consequently conjugated with glucuronic acid by uridine diphosphate glucuronosyltransferase (UGT) (4, 5). In long-term treated patients, 30–50% of carbamazepine-diol is excreted directly into urine (5). Even though CBZ and VPA have been in use since the 1960s (1, 6), there is no consensus regarding the clinical relevance of VPA effects on carbamazepine metabolism (5), with both increases and decreases in the CBZ level ha- ving been observed (7). Carbamazepine-10,11- epoxide level was reported to be increased with concurrent use of valproate (3, 5, 7, 8). CBZ is known as an inducer of cytochro- me CYP3A4, CYP2C and epoxide hydrolase (9), and its own metabolism is susceptible to autoinduction after repeated administration (2, 7, 8). The autoinduction is reported to be fi- nished after onemonth of drug administration (5). CBZ-E also induces its own metabolism in a way similar to CBZ (10). VPA is an inhibitor of epoxide hydrolase (1, 9, 11) and nonspe- cifically inhibits all steps of the epoxide-diol pathway of CBZ metabolism in children (12). Significant positive correlations have been found between the VPA level and CBZ-E/CBZ ratio, as well as the CBZ level/dose ratio in children (13). The aimwas to study the effect of valproic acid on carbamazepine concentration during long-term treatment in pediatric epileptic pa- tients. Material and method Request and reply forms for therapeutic drug monitoring of antiepileptic drugs exa- mined during the period 1997–2002 were used as a data source. A total of 262 of sam- ples taken predose obtained from 175 pedia- tric patients (i. e., younger than 15 years) were included. The characteristic of the cohort is given in Table 1. Eleven patients treated with both CBZ monotherapy and CBZ + VPA were included in both groups. These 11 patients who served as their own control were also analyzed in detail. Inclusion criteria: Long-term treatment with slow-release forms of carbamazepine (Timonil, Tegretol, Neurotop) or valproic acid (Depakine, Orfiril, Convulex). Exclusion criteria: Suspected non-com- pliance (i. e., a plasma level of CBZ <1mg/L and of VPA <10mg/L), once daily treatment regimen. Patients treated with other drugs were excluded with an exception of magne- sium, nootropics (piracetam, pyritinol), and vitamins. Dosage (absolute daily dose, dose related to body weight), plasma levels of CBZ, CBZ-E, CBZ level/dose ratio, CBZ-E level/dose ratio, CBZ-E/CBZ, and CBZ + CBZ-E were evaluated. The distribution of plasma levels according to the therapeutic range 4–9mg/L and the incidence of adverse drug reactions, such as nystagmus, dizziness, bradypsychia, ataxia, headache, and nausea, were analyzed. The frequency of seizures was divided into four categories: occurrence of seizures daily, monthly, several seizures per year, and being seizure-free more than one year. Statistics we- re calculated from answered questions only. All samples were included in patients exa- mined repeatedly, while means per patient were used in a detailed analysis of 11 indivi- duals who served as their own control. Analysis of plasma levels CBZ and CBZ-E plasma levels were deter- mined using high-performance liquid chro- matography (HPLC) (14). Plasma levels of VPA were assayed with gas-liquid chromatography (GLC) (15). Both methods were fully validated and participated in external quality control schemes – RfB Referenzinstitut für Bioanalytik. Statistics Differences between means were com- pared using the Student’s t-test (two-tailed). The Chi-square test was used to analyze the distribution of plasma levels according to the therapeutic range (16) and for seizure frequen- cy (17). Results The patients on the CBZ + VPA regimen were treated with significantly higher daily doses (absolute as well as related to the body weight) while mean plasma levels of CBZ and CBZ-E were not different (Table 2). The dose of valproic acid was (mean ± SD) 691 ± 218mg, DBW was 25.15 ± 11.83mg.kg -1 , and VPA level was 52.57 ± 17.25mg.L -1 .