Klinická farmakologie a farmacie – 2/2021

KLINICKÁ FARMAKOLOGIE A FARMACIE / Klin Farmakol Farm 2021; 35(2): 49–53 / www.klinickafarmakologie.cz 52 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 Liu et al (13) also mentioned a significant decrease in the CBZ level/dose ratio in the presence of VPA. An increase in the CBZ-E level and CBZ-E/CBZ ratio in CBZ + VPA reported by Liu et al (13) and Potter et al (3) was not observed in our study. Liu et al further described a CBZ-E/dose increase while we found a significant decrea- se. The effect of a different drug formulation is questionable. Two steps of CBZ-VPA interaction might explain the conflicting reports: initially, the CBZ level rose because of either enzymatic inhibition or protein binding displacement due to VPA, followed by enzymatic indu- ction due to CBZ. Enzymatic inhibition is generally caused by competition at the en- zyme site (2) and occurs immediately after treatment initiation, while enzymatic indu- ction requires the synthesis of a new pro- tein, which may take several days or weeks (13). This mechanism is supported by the finding of Liu et al (13) who found a signifi- cant decrease in the CBZ level/dose ratio in CBZ+VPA and together positive correlation between this ratio and VPA level. They also described a significantly increased CBZ free fraction as a result of relatively decreased total CBZ level with almost unchanged free CBZ concentration. An increase in the free fraction described by Levy et al (18) was also suggested as a reason for CBZ level decrease in the presence of VPA. A third mechanism involved may be in- complete absorption described in high doses of CBZ (10) which might be deepened with lower bioavailability of retard tablets, that we found in our previous study (22). Lower bioavailability might also explain the lower CBZ level/dose ratio when compared with the observation by Liu et al (13). Similarly to us, Potter et al (3) pointed out that clinicians tended to target concentrations at the lower end of the therapeutic range. When therapeutic drugmonitoring is per- formed, the dose of CBZ is stepwise increased according to the TDM outcomes, similar CBZ levels are reached, and the clinical effect of the interaction is thus eliminated. The TDM outcomes must be interpreted in relation with dosage, otherwise incorrect conclusions might be drawn. Limitations: Non-adherence of physici- ans to some questions on the request forms (mentioned also by Morris et al. (23), espe- cially those regarding seizure frequency or occurrence of ADRs, represents a difficulty for data evaluation. In the case of ADRs, we cannot distinguish whether they were not reported because they did not occur or be- cause of simple non-adherence. Considering this fact, we decided to show the percent- age of the incidence of ADRs from the whole group. Potential under-reporting of ADRs or inaccuracies regarding seizure frequency on the request form are inherent to the retrospective and pragmatic nature of this study. Tab. 7. The cohort characteristics of 11 patients treated with both CBZ and CBZ+VPA No. gender age [yr] body weight [kg] CBZ dose [mg] CBZ DBW [mg/kg] CBZ CBZ + VPA CBZ CBZ + VPA 1 F 9 26 200 200 7.69 7.69 2 M 5 23 288 500 14.32 17.45 3 F 10 33 300 375 9.68 10.97 4 F 7 27 325 375 13.18 11.36 5 F 8 27 375 675 18.75 22.27 6 M 11 31 375 600 13.06 17.71 7 F 7 20 412 375 20.09 19.74 8 M 10 43 488 638 11.72 14.56 9 M 10 30 525 525 18.10 17.50 10 M 12 50 525 750 10.71 15.00 11 M 10 24 600 700 31.58 25.83 mean ± SD 9 ± 2 30 ± 8 401 ± 122 519 ± 172** 15.4 ± 6.6 16.4 ± 5.2** **p <0.01, DBW – dose related to body weight Tab. 8. The dosage and plasma levels of valproic acid No. dose [mg] DBW [mg/kg] plasma level [mg/L] 1 75 2.9 33.0 2 750 26.7 57.5 3 525 15.4 57.2 4 500 15.2 42.7 5 750 25.0 68.8 6 750 21.9 46.6 7 500 26.3 40.0 8 438 9.9 39.8 9 250 8.3 39.1 10 500 10.0 36.0 11 600 22.5 35.8 mean ± SD 513 ± 211 16.7 ± 8.2 45.1 ± 11.3 DBW – dose related to body weight Tab. 9. Plasma levels of carbamazepine, carbamazepine-10,11-epoxide and CBZ-E/CBZ ratio in 11 patients treated with both CBZ and CBZ + VPA No CBZ level [mg/L] CBZ-E level [mg/L] CBZ-E/CBZ CBZ CBZ + VPA CBZ CBZ + VPA CBZ CBZ + VPA 1 5.2 3.8 0.6 0.4 0.12 0.11 2 6.0 4.6 1.18 0.8 0.19 0.19 3 4.7 5.1 0.9 0.7 0.19 0.14 4 4.6 2.4 0.7 1.1 0.15 0.46 5 6.5 6.5 1.6 1.8 0.25 0.28 6 4.8 5.0 0.25 1.1 0.05 0.21 7 4.4 5.0 1.4 2.3 0.32 0.46 8 5.7 6.6 1.15 1.7 0.20 0.28 9 8.6 6.7 0.9 1.1 0.10 0.16 10 4.0 4.6 0.8 0.8 0.20 0.17 11 5.3 5.6 1.7 0.8 0.32 0.14 mean ± SD 5.4 ± 1.3 5.1 ± 1.2 1.0 ± 0.4 1.1 ± 0.6 0.19 ± 0.08 0.24 ± 0.12