Klinická farmakologie a farmacie – 2/2021

www.klinickafarmakologie.cz / Klin Farmakol Farm 2021; 35(2): 49–53 / KLINICKÁ FARMAKOLOGIE A FARMACIE 49 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 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 Blanka Kořístková 1, 2 , Milan Grundmann 1, 2 , Hana Brozmanová 1, 2 , Ivana Kacířová 1, 2 1 Ústav klinické farmakologie, Lékařská fakulta, Ostravská Univerzita, Ostrava 2 Oddělení klinické farmakologie, Ústav laboratorní medicíny, Fakultní nemocnice Ostrava The effect of valproic acid (VPA) on plasma level of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) in long-term treatment was evaluated. Method: A total of 262 samples were obtained predose from 175 pediatric patients (<15 years). Daily dose (PDD), dose related to bodyweight (DBW), plasma levels (PL) of CBZ, CBZ-E, CBZ level/dose ratio, CBZ-E level/dose ratio and CBZ-E/CBZ ratio, the distri- bution of PL according to the therapeutic range 4–9mg/L, and seizure frequency were compared. A detailed analysis was done in 11 individuals who served as their own control. Results (given as mean ± SD): Patients on a CBZ + VPA regimen were treated with higher daily doses: PDD 557 ± 204 vs. 400 ± 187mg, respectively, p <0.001; DBW 20.2 ± 10.5 vs. 13.5 ± 5.8mg/kg, respectively, p <0.001. The mean CBZ PL and the distribution of PL according to the therapeutic range were not different: 5.1 ± 1.4 vs. 5.3 ± 1.9mg/L, respectively. There was 86% of therapeutic PL CBZ + VPA and 77% in monotherapy. No toxic level was found. CBZ-E PL remained unchanged in CBZ + VPA (1.2 ± 0.8 vs. 1.1 ± 0.9mg/L, respectively) as did the CBZ-E/CBZ ratio (0.24 ± 0.12 vs. 0.22 ± 0.19, respectively). The CBZ level/dose was decreased in CBZ + VPA: 10.3× 10 -3 ± 4.2×10 -3 vs. 14.9×10 -3 ± 6.4×10 -3 mg×L -1 /mg, respectively, p<0.001; so was the CBZ level/DBW: 0.31 ± 0.17 vs. 0.44 ± 0.19mg×L -1 /mg×kg -1 , p <0.001. These findings suggest an inductive effect of VPA on CBZ metabolism. Similar outcomes were found in 11 individuals who served as their own control: CBZ level/dose 10.9×10 -3 ± 3.7×10 -3 vs. 15.0×10 -3 ± 5.7×10 -3 , respectively, p <0.01; CBZ level/DBW 0.35 ± 0.10 vs. 0.40 ± 0.14, respectively, p <0.05. Dose-dependent adverse drug reactions (ataxia, headache) were reported in four individuals on CBZ monotherapy. No difference in the mean PL of CBZ or CBZ-E was found, while the CBZ-E/CBZ ratio and CBZ-E level/dose ratio were increased: 6.8×10 -3 ± 1.6×10 -3 vs. 3.1×10 -3 ± 3.6 ×10 -3 , and 0.32 ± 0.06 vs. 0.21 ± 0.20, p <0.05). No difference in seizure frequency was found. Conclusion: The CBZ-VPA interaction is considerable, but it is sufficiently eliminated due to TDM dose adjustment. Key words: carbamazepine, carbamazepine-epoxide, valproic acid, drug-drug, interaction, slow-release drug formulations. Vliv kyseliny valproové na hladinu karbamazepinu a karbamazepin-10,11-epoxidu při dlouhodobé léčbě přípravky s pomalým uvolňováním u dětí, význam TDM Účel studie: Hodnocení vlivu kyseliny valproové (VPA) na hladinu karbamazepinu (CBZ) a karbamazepin-10,11-epoxidu (CBZ-E) při dlouhodobé léčbě přípravky s pomalým uvolňováním. Metoda: U 262 vzorků odebraných před podáním od 175 dětských pacientů (<15 let) byla hodnocena celková denní dávka (PDD), dávka na kg (DBW), koncentrace CBZ, CBZ-E, poměry CBZ koncentrace/PDD, CBZ-E koncentrace/PDD, CBZ-E/CBZ a rozložení koncen- trací CBZ ve vztahu k terapeutickému rozmezí 4–9mg. Podrobná analýza byla provedena u 11 pacientů, kteří byli vlastní kontrolou. KORESPONDENČNÍ ADRESA AUTORA: PharmDr. Blanka Kořístková, Ph.D., blanka.koristkova@osu.cz Oddělení klinické farmakologie, Ústav laboratorní medicíny, Fakultní nemocnice Ostrava, tř. 17. listopadu 1 790, 708 52 Ostrava Cit. zkr: Klin Farmakol Farm 2021; 35(2): 49–53 Článek přijat redakcí: 26. 5. 2021 Článek přijat k publikaci: 15. 6. 2021