## 4 Discussion
Higher levetiracetam clearance estimates (e.g., 5.9 L/h) are reported in studies of epilepsy patients who are not critically ill, such as the large study by [PERSON] et al. [41]. In that study the median eGFR estimate was 97.6 (mL/min)/1.73m\({}^{2}\), while in our study the median eGFR estimate of all participants was much lower 81.62 (mL/min)/1.73 m\({}^{2}\). The range of eGFR values in our study was from 18.8 mL/min to 123.3 mL/min, whereas for the study of [PERSON] et al. the reported eGFR was as high as 189 mL/min [41]. The issue that our patients had poorer renal function compared with other studies reporting higher levetiracetam clearance studies, may explain the low clearance values found in our study. The individual fitting plots for the 14 patients are shown in Figure S2. These fitting results demonstrate the adequacy of the descriptiveness of the developed model. Using only three blood samples per patient and data from only 14 subjects, it was possible to develop a model that describes the pharmacokinetics of levetiracetam. For comparison purposes, simulations were performed for the other relevant models in the literature. The model estimates (structural model, mean model parameter, between-subject variabilities, error model) were those reported in the literature (summarized in Table S1) and were kept fixed, while the covariates were related to our study patients. Then, it was attempted to examine the adequacy of fitting of these literature models to the concentration-time data of the 14 patients in this study. VPCs and normalized prediction distribution errors (NPDEs) plots were constructed (Figures S3 and S4 in the Supplementary Material). Figures S3 and S4 reveal that some literature models adequately fit the C-t data of our study, The best overall performance was observed for the models of [PERSON] et al., [PERSON] et al., [PERSON] et al., and [PERSON] et al. [23; 26; 41; 43]. However, for all these models, the performance was not better than for our model. The positive correlation (correlation coefficient equal to 0.76) between eGFR and levetiracetam clearance, shown in Figure 3, indicates a lower elimination capacity in patients with renal dysfunction. This result is consistent with the prescribing information for levetiracetam, which recommends adjusting the levetiracetam dose based on renal function [24; 41; 42]. At this point, it should be mentioned that several other covariates related to patient disease severity have been tested for their potential role in influencing levetiracetam pharmacokinetics. However, none of these covariates were found to have a significant effect on any of the model parameters of levetiracetam (i.e., \(p\) > 0.05). In a further step, the developed population pharmacokinetic model was used to evaluate the effects of impaired renal function on the kinetics of levetiracetam (Figure 4). In the simulated \"healthy\" subjects, the dosing regimens resulted in levetiracetam levels that were within the therapeutic range (Figure 4a), which is consistent with the literature [40]. The same levetiracetam doses resulted in significantly increased concentration levels in patients with impaired renal function, such as a 50% decrease in clearance and in the study patients (Figure 4b,c), as well as a higher risk of drug toxicity. It is worth noting that this observation is consistent with recommendations in the literature regarding treatment with levetiracetam. It is of note that if seizures cannot be controlled even with high concentrations of levetiracetam, increasing the dose above 2000 mg/day will not benefit the patient; instead, clinicians should consider switching to an antiepileptic drug with a different mechanism of action [23; 42]. These findings highlight the importance of dose adjustment in patients depending on their eGFR [45; 46]. In general, monitoring levetiracetam serum concentrations as part of therapeutic drug monitoring, ensures more effective and safer dosing regimens.