LEV displays linear elimination kinetics; therefore, dose changes produce predictable changes in serum concentrations [6–9], but some studies failed to show the relationship.
Sheinberg et al. reported no correlation between administered dose and serum drug level in their study even though they found no correlation between LEV serum levels and clinical efficacy . Similarly, May et al. stated that the relationship between LEV dose per body weight and serum concentration deviates significantly from linearity .
In our study, the LEV dose and blood concentration positively and significantly correlate differently from these reports. LEV concentrations were positively correlated with dose; however, variability has been shown among patients receiving the exact dosage for body weight. May et al. explained this individual variation in parts by effects of age and co-medication .
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 significant, especially in the monotherapy group. The correlation value between the daily dose and the serum level in the patients with co-medication was poorly significant. This may explain the possibility of alteration in LEV concentration when concomitant antiepileptic medications are used .
The drug is not implicated in any drug interactions due to low hepatic metabolism, and previous studies have reported no significant 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 influence 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 . 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 .
In our study, the dose was significantly 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 co-medication 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 first year of life is 60–70% higher than in adults. Thus children should receive higher LEV dosages to achieve comparable serum drug concentration . May et al. found similar results and concluded that LEV dose was significantly dependant on age .
Studies reported that LEV concentrations were positively correlated with age, but gender had no significant impact on LEV concentration . In our study, age and gender had no significant effect on LEV concentration in both groups.
Despite LEV’s predictable kinetics, its target therapeutic ranges have not been well established. The International League Against Epilepsy committee set the LEV reference range for an average of 12 − 46 µg/mL . A reference serum range of 0.11–55.31 µg/mL was perceived for the LEV daily dosing of 10.20–77.0 mg/kg in our study. The mean drug concentration in our patients is within the ILAE established reference range, but concentration monitoring revealed children with serum concentrations below (56.4%) and above 3(2.1%) the therapeutic range. All cases in our study had the typical range of drug dose per body weight with no side effects.
So we point out that a range of 12–46 µg/mL is not practical for most patients. Due to its tolerability over an extensive concentration range, clinical assessment without measuring drug concentrations remains the monitoring strategy for patients with epilepsy on LEV therapy.