Levetiracetam Serum Concentrations in Pediatric Patients: Is There a Role in Clinical Decision Making?

Monitoring of levetiracetam is not frequently used in clinical practice. This study evaluated the LEV blood level concentrations, correlation with dose, and co-medication effect to decide the need for blood concentration monitoring in pediatric patients. The children with epileptic seizures on levetiracetam therapy, aged one month-18 years, were enrolled and evaluated for gender, age, body weight, daily drug dose, comedication, and drug concentration records. 57.9% of one hundred and forty patients were on monotherapy. The mean dose of LEV was 35.40 mg/kg/day, while the mean drug concentration was 14.06 μg/ mL. The correlation between the dose and the serum concentration in the polytherapy group was poorly signicant, whereas it was positive and highly signicant in the monotherapy group. The mean drug concentration was within the established reference range, but concentration monitoring revealed children with serum concentrations below and above the therapeutic range. All cases in our study had the typical range of drug dose per body weight with no side effects. Conclusion: We point out that monitoring is not practical for most patients. Due to its tolerability over an extensive concentration range, the clinical assessment remains the monitoring strategy for patients with epilepsy on LEV therapy.


Introduction
The treatment of epilepsy requires individualizing drug doses to increase e cacy while avoiding adverse events. In clinical practice, the treatment of epilepsy is based on effectiveness and tolerability. However, clinical effects can be anticipated by measuring antiepileptic drug (AED) serum concentrations [1]. Drug monitoring is often recommended in pediatric patients for certain AEDs due to signi cant interindividual differences and unpredictable drug disposition [2]. Levetiracetam (LEV) is a second-generation broadspectrum AED, effective in threatening multiple seizure types in children. The lack of effect on cytochrome P450 and its minimal protein binding reduce its pharmacokinetic interactions. In patients receiving LEV, blood level monitoring is not frequently used in clinical follow-up due to its favorable pharmacokinetics and the lack of reference for the drug's therapeutic range [3][4][5]. This study evaluated the LEV blood level concentrations, correlation with dose, and co-medication effect to decide the need for blood concentration monitoring in pediatric patients.

Methods
The institutional ethics committee approved this retrospective study (159-22.05.2020). LEV serum concentrations were determined using a kit with high-performance liquid chromatography in a single laboratory. We retrospectively searched the institution's database for children with epileptic seizures on LEV treatment as monotherapy or polytherapy between January 2018-January 2020. A hundred and forty children with epilepsy aged one month-18 years were enrolled in the study. They presented different types of epilepsy syndromes. In the management of epileptic patients, the drug serum concentration is determined a month after treatment initiation or a month after a change in dosage. We evaluated the patient's gender, age, body weight, daily drug dose, comedication, and drug blood level records. Patients on LEV were divided into two groups; monotherapy and polytherapy group.

Statistical Analysis
Descriptive statistics were presented as frequency (percentage) for categorical variables and mean±SD (median, min, max where necessary) for numerical variables. Chi-square test with Monte Carlo Exact method was used to determine the relations between the categorical variables. Mann-Whitney U test was used to compare drug groups since the distribution of the continuous variables was not normal by the Shapiro-Wilk test. Spearman's Rho correlation coe cients were calculated to see the relations between the dose and the drug's serum level. The associations were visualized by scatter plots. p<0.05 value was considered a statistically signi cant result for 5% type-I error in all analyses. The study's comments were performed by SPSS 20.0 (IBM Inc, Chicago, IL, USA) software.

Power Analysis
The apriori power analysis was performed by GPower 9.1.2 software. The effect size was calculated as 0.58 using the dose level of LEV in a pilot study. Choosing a one-tailed t-test for the Mann-Whitney U test for independent samples, the sample size was 54 & 76 for each group (total 130). We considered the power as 0.80, the error as 5%, and the allocation ratio as 1.5.

Results
One hundred forty epilepsy patients, aged between 1 and 18 years, were included in the study. 53.6% of the patients were girls, and the mean age was 9.45 ± 4.91 years. Eighty-one (57.9%) of the patients were on monotherapy. The others were on polytherapy. The most commonly used concomitant drugs were valproate, clobazam, carbamazepine. We found that the mean dose of LEV was 35.40 ± 16.53 (10.2-77.0) mg/kg/day, while the mean drug level in blood was 14.06 ± 11.14 (0.1-55.3) µg/ mL. A signi cant and positive correlation was found between the drug dose and the drug level in the blood. (R = 0.484; p <  We compared the dose and the serum level of the drug in the monotherapy and polytherapy groups. The patients' age and gender did not differ signi cantly (p = 0.775), (p = 0.634) between the groups. We found the dose to be considerably higher in the patients with co-medication (p = 0.001). The mean dose was calculated as 31.51 ± 15.62 mg/kg/day in the monotherapy group, while it was 40.76 ± 16.38 mg/kg/day in the polytherapy group. The serum level was higher in the polytherapy group (18.08 ± 12.01 µg/mL), but the difference was not signi cant (p = 0.485). The correlation value between the daily dose and the serum level in the patients with co-medication was poorly signi cant (R = 0.293; p = 0.024), whereas the relation between the dose and serum level in the monotherapy group was positive and highly signi cant (R = 0.619; p < 0.001)( Table 2)( Fig. 2 and Fig. 3). We compared LEV plasma level and LEV dose values according to age groups. Drug dose differed signi cantly according to age groups (p < 0.001). The drug dose value was relatively high in patients aged 0-1 year and moderate in the 7-12 age group. We observed that the dose value decreased signi cantly as the age increased (> 12 years old). Serum drug levels did not differ signi cantly by age groups (Table 3). We divided patients into three groups as < 12, 12-46 ve > 46 µg /mL according to the therapeutic range. Gender, age, presence of concomitant drug did not differ signi cantly according to plasma level groups. We found that the drug dose was signi cantly lower in the patient group with plasma level < 12 µg/mL than the other groups (p < 0.001) ( Table 4). As LEV is mainly given as add-on therapy, we investigated drug interaction with LEV. We divided patients into two groups; monotherapy and polytherapy. We realized that correlation was positive and highly signi cant, especially in the monotherapy group. The correlation value between the daily dose and the serum level in the patients with co-medication was poorly signi cant. This may explain the possibility of alteration in LEV concentration when concomitant antiepileptic medications are used [11].
The drug is not implicated in any drug interactions due to low hepatic metabolism, and previous studies have reported no signi cant interactions between LEV and other AEDs [12,13]. Nonetheless, there are studies indicating that drug interactions may still occur out. The mechanism is not well understood. The data suggest that concomitant AED, especially enzyme-inducing AED, has a moderate in uence on the LEV kinetics by the possible increase of clearance of LEV in the presence of concomitant AED [8, 11, 14-16].
Mathew et al. found that patients receiving concomitant enzyme-inducing AED had drug serum concentrations lower than enzyme-inhibiting AED or no interfering AEDs [16]. Also, Stepanova et al. suggested interaction between LEV and concomitant AEDs as patients on polytherapy required a higher dose of LEV to achieve similar blood levels and provided support for the use of drug level determination [17].
In our study, the dose was signi cantly high in the polytherapy group, but plasma concentration did not differ between the two groups. So the data and our study results may indicate a modest effect of comedication on the LEV kinetics, informing that patients on polytherapy required a higher dose of LEV to achieve similar blood levels.
According to age groups, serum drug concentration was not different, but the dose was high in the 0-1years group. Young children need a higher LEV dose per weight to achieve comparable LEV concentration [15,18]. Pharmacokinetic differences for the drug between age groups have been described. LEV clearance during the rst year of life is 60-70% higher than in adults. Thus children should receive higher LEV dosages to achieve comparable serum drug concentration [15]. May

Conclusions
Because of the wide therapeutic range, predictable serum concentration changes, possible minimal drug interaction, and low prevalence of side-effects, LEV monitoring is unnecessary for optimizing drug therapy even in speci c groups such as young age and patients on polypharmacy. LEV dosing should be guided by clinical e cacy and adverse effects outcomes, making LEV easy to use in pediatric patients. Ethics approval: Ethical approval was waived by the local Ethics Committee of University.  (7): 1239-76. Figure 1 Page 13/14

Figures
The correlation between the serum level and dose of levetiracetam in all patients.

Figure 2
The correlation between the serum level and dose of levetiracetam in patients with comedication.