Klinická farmakologie a farmacie – 2/2021

www.klinickafarmakologie.cz / Klin Farmakol Farm 2021; 35(2): 49–53 / KLINICKÁ FARMAKOLOGIE A FARMACIE 51 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 concentration ratio of CBZ-E/CBZ was unchanged. The CBZ level/dose ratio as well as CBZ-E level/dose ratio were lower in patients on the CBZ+VPA regimen (Table 3). This sug- gests an increased clearance of CBZ and CBZ-E. The distribution according to the thera- peutic range was similar in both regimens. No level was found above the older upper margin, i. e., 12mg/L. When the CBZ + CBZ-E level was counted together, 6 (3%) levels above 12mg/L in CBZ monotherapy were found (Table 4). Generally, CBZ levels tended to target concen- trations at the lower end of the therapeutic range (Fig. 1). Adverse drug reactions were found in four individuals on CBZ monotherapy (Table 5). No difference in mean CBZ or CBZ-E levels was found when compared with patients without toxic events, while the CBZ-E/CBZ ra- tio and CBZ-E level/dose ratio were increased (6.82×10 -3 ± 1.61×10 -3 vs. 3.14×10 -3 ± 3.62× 10 -3 , and 0.321 ± 0.061 vs. 0.214 ± 0.197, p <0.05). Information on seizure frequency was given in 148 request forms (56%). The diffe- rence between CBZ and CBZ+VPA was not significant (Table 6). Analysis of 11 patients who served as their own control The cohort characteristic and dosage of CBZ in 11 patients that served as their own control is given in Table 7. The VPA dosage and plasma levels are given in Table 8. Six patients only reached the therapeutic range 50–100mg/L. Patients treated with CBZ+VPA received significantly higher daily doses, while CBZ levels, CBZ-E levels, and CBZ-E/CBZ ratios were not different. All levels reached the therapeu­ tic range 4–9mg/L in monotherapy, while two dropped below when VPA was added (Table 9). A significantly lower mean CBZ level/ dose ratio as well as mean CBZ level/DBW ratio were found in the CBZ+VPA group (Table 1). No adverse drug reactions were reported in this cohort. Discussion The CBZ plasma level and the distribution of plasma levels according to the therapeutic range were similar in both regimens. The lack of an effect of VPA on plasma level of CBZ is apparent at first sight. However, these findings are a result of significantly higher daily doses as well as DBW in the CBZ+VPA group. The CBZ level/dose ratio was significantly decreased in CBZ + VPA in the whole cohort as well as in 11 patients who served as their own control. This reflects increased CBZ clearance. Similar findings were described by Levy et al (18) in a cohort of seven patients (both children and adults), by Liu et al (13) in children, and by Rambeck et al (19) in adults. Shoeman et al (20) also found a decreased CBZ level which, however, was not significant. By contrast, Svinarov et al (12) found an increased CBZ level/dose ratio in CBZ + VPA in children, but a decreased ratio in adults two months after treatment initiation. Potter et al (3) reported similar mean CBZ concentrations in both CBZ and CBZ + VPA groups, but information on the dosage is lacking. Bernus et al (21) reviewed five studies with no appreciable change in the CBZ plasma level. Tab. 1. The characteristic of the cohort CBZ alone CBZ+VPA number of patients 143 32 number of samples 209 53 age [yr] † 8.8 ± 3.2 10.0 ± 2.6** weight [kg] † 32.2 ± 13.6 30.7 ± 11.1 † values are given as mean ± SD, ** p <0.01 Tab. 2. The dosage and plasma levels of carbamazepine and carbamazepine-10,11-epoxide CBZ CBZ+VPA difference dose [mg] 400 ± 187 557 ± 204 39% *** dose related to body weight [mg/kg] 13.5 ± 5.8 20.2 ± 10.5 50% *** CBZ level [mg/L] 5.3 ± 1.9 5.1 ± 1.4 −3% CBZ-E level [mg/L] 1.1 ± 0.9 1.2 ± 0.8 10% CBZ-E/CBZ 0.22 ± 0.19 0.24 ± 0.12 12% CBZ+CBZ-E [mg/L] 6.3 ± 2.3 6.3 ± 1.6 −1% The values are given as mean ± SD, *** p < 0.0001; ** p < 0.01 Tab. 3. Level/dose ratios of carbamazepine and carbamazepine-10,11-epoxide CBZ CBZ+VPA difference CBZ level/dose [mg × L -1 /mg] 14.9 × 10 -3 ± 6.4 × 10 -3 10.3 × 10 -3 ± 4.2 × 10 -3 −31%*** CBZ level/DBW [mg × L -1 /mg × kg -1 ] 0.44 ± 0.19 0.31 ± 0.17 −29%*** CBZ-E level/dose [mg × L -1 /mg] 3.2 × 10 -3 ± 3.6 × 10 -3 2.4 × 10-3 ± 1.5 × 10 -3 −24%* CBZ-E level/DBW [mg × L -1 /mg × kg -1 ] 90.1 × 10 -3 ± 90.3 × 10 -3 72.8 × 10-3 ± 52.0 × 10 -3 −19% The values are given as mean ± SD; *** p <0.0001; * p <0.05, DBW – dose related to body weight Tab. 4. The distribution of CBZ concentrations related to therapeutic range (TR) 4–9mg/L regimen plasma level 0–3.9 4–9 >9 >12mg/L CBZ level CBZ 49 (23%) 153 (73%) 7 (3%) 0 CBZ + VPA 10 (19%) 43 (81%) CBZ+CBZ-E level CBZ 24 (11%) 157 (75%) 28 (13%) 6 (3%) CBZ + VPA 4 (7.5%) 49 (92.5%) Tab. 5. The type of adverse drug reaction in relation with CBZ and CBZ-E levels and their ratios in order to CBZ level Patient No. CBZ level CBZ-E level CBZ-E/CBZ CBZ + CBZ-E adverse drug reaction 1 2.8 1.0 0.357 3.8 headache 2 5.1 1.3 0.255 6.4 ataxia 3 8.1 2.3 0.284 10.4 ataxia 4 10.1 3.9 0.386 14 ataxia Tab. 6. Seizure frequency NR/total daily monthly yearly none CBZ 90/209 10 (8%) 37 (31%) 51 (43%) 10 (18%) CBZ + VPA 24/53 5 (21%) 9 (31%) 12 (41%) 5 (7%) NR not reported. Percentages are calculated from answered questionnaires only.