## 4 Discussion  
The aim of this study was to investigate the pharmacokinetics of levetiracetam in critically ill intensive care adult patients and to identify possible pathophysiological factors affecting the kinetics of levetiracetam and, consequently, clinical outcome. A clinical study was conducted on 14 patients from an intensive care unit of a tertiary care hospital in whom levetiracetam was administered for either prophylactic or therapeutic reasons. Eleven patients had stable renal function according to the physicians' assessment, while the remaining three had acute renal injury. Having stable renal function does not mean that their renal function was normal, i.e., a glomerular filtration rate greater than 90 mL/min. In these 11 patients, the median eGFR was 97.7 mL/min and three patients (3 of 11) had an eGFR of less than 70 mL/min. In the patient group with acute kidney injury, the median eGFR was 45.3 mL/min. Overall, only five patients had an eGFR greater than 90 mL/min  
Figure 4: Simulated concentration vs. time profiles of levetiracetam in normal subjects (**a**), renal impairment 50% (**b**), and for the patients of the study (**c**). In each group, 500 individuals were generated. In the case of the normal renal function subjects (**a**) the utilized model parameters were obtained from study [23]. For the 50% renal impairment the model parameters were similar to (**a**), except for clearance, which was set at 50% of the reported value. For the study patients, the parameter values listed in Table 2 were used. The dosing regimen for each subject was identical to that actually used in the ICU (Table 1). Figure 3: Relationship between levetiracetam clearance and the estimated glomerular filtration rate (eGFR) according to the Chronic Kidney Disease Epidemiology collaboration mathematical formula (CKD-EPI eGFR). The eGFR axis is expressed in dual units: mL/min and L/h. The correlation coefficient between levetiracetam clearance and eGFR was equal to 0.76. (i.e., normal renal function), and the remaining nine patients ranged from mild to severe loss of renal function. Using measurements of serum concentrations in these patients, a population pharmacokinetic model for levetiracetam was developed. The final model for levetiracetam thus derived, referred to a linear one-compartment model with intravenous infusion administration and first-order elimination. This one-compartment model was consistent with other published levetiracetam studies conducted in children, adults, and elderly patients (Table S1) [23; 24; 25; 26; 27; 41; 42; 43]. It should be mentioned that loading doses of levetiracetam were used. However, in the model development and the simulations (Figure 4) performed in this study, loading doses were not considered because they do not alter steady-state plasma levels, but only shorten the time required to reach these plateau levels. Among the covariates tested, only measures of renal function showed a significant effect on clearance. Among the different eGFR measures explored, CKD-EPI eGFR was selected because it resulted in the lowest \(p\)-value (\(p\) = 0.00164, Table 2) and is one of the most commonly used eGFR measures. No significant relationships were found for other scores describing disease severity (such as APACHE II or SOFA), likely due to the small number of patients participating in the study. Levetiracetam clearance in this study (1.45 L/h, Table 2) was lower than the values reported in the literature (from 2.17 L/h to 6.87 L/h, Table S1). This finding may be attributed to the fact that our study included patients with impaired renal function. Moreover, the clearance estimates would also increase with increasing eGFR of our patients, as beta_eGFR had a positive sign (equal to 0.25, Table 2) [44]. In the study by [PERSON] et al., which also recruited critically ill adult patients, the estimated clearance was 2.51 L/h [7].