This study is, to the best of our knowledge, the first to propose alternative dosing regimens for levetiracetam in critically ill patients with ARC. Dosing simulations suggest the need to administer up to 6000 mg of levetiracetam daily to reach the target plasma level. Our results indicate that it is necessary to optimize the dosage regimen in terms of increasing the dose and/or infusion time to reach the target plasma concentrations in this group of patients. Considering this evidence, it is worth wondering whether we are using levetiracetam adequately in critically ill patients, especially in those with ARC. This should be an issue to be taken into account in daily clinical practice, because ARC has been identified in 20–65% of ICU patients and in up to 85% of neurocritical patients [6,7,8,9,10].
Currently, the reference range for levetiracetam trough concentrations has been stablished by the ILAE in 12–46 mg/L . However, studies carried out in critically ill patients have shown that these plasma concentrations are not achieved with the authorized adult dosing regimen. To date, four PPK studies of levetiracetam have been identified in neurocritical care patients. Spencer et al.  included 12 adult patients who received levetiracetam. They estimated a higher levetiracetam CL and a shorter half-life compared with previously published results in healthy volunteers. Just one patient, with renal impairment (CrCl 42 mL/min), achieved a steady-state trough concentration greater than 6 mg/L. Sime et al.  developed a population pharmacokinetics model in 30 critically ill patients with severe TBI or SAH without renal dysfunction. For every 40 mL/min/1.73 m2 increase in urinary CrCl, levetiracetam CL increased by 50% and the median trough concentrations were reduced by 50%. They performed dosing simulations with dosages ranging from 1000 mg every 12 h to 2000 mg every 8 h and concluded that for urinary CrCl greater that 120 mL/min/1.73 m2, none of the simulated regimens had a probability of 80% or above of achieving trough concentrations higher than 12 mg/L. Similarly, Ong et al.  developed a PPK model in 20 neurosurgical patients. They also performed Monte Carlo simulations showing a low probability of reaching trough concentrations > 6 mg/L with the 500 mg twice daily dosing regimen. Finally, our group also reported a population pharmacokinetic model in 27 critically ill patients , not restricted to neurocritical patients. CrCl demonstrated a significant influence on the levetiracetam CL. Dosing simulations showed that the administration of at least 500 mg every 8 h or 1000 mg every 12 h would be needed in patients with normal renal function and that higher doses or shorter dosing interval would be needed in patients with ARC.
According to these PPK models, the dosage regimen of 500 mg every 12 h is insufficient to achieve a PTA of at least 80% in ICU patients with a normal renal function. However, this is a widely used dosage in clinical practice, especially in the prophylactic context, where between 34 and 100% of patients received this dosage [17,18,19,20]. Furthermore, the maximum dosage approved for levetiracetam, 3000 mg daily in short infusion, also resulted in subtherapeutic levels in patients with ARC. Our results confirm that the target plasma levels would only be reached in ARC patients with the administration of at least 3000 mg in 4-h infusion (in patients with CrCl of 160 mL/min) or in continuous infusion (in patients with CrCl of 200 mL/min). Although extended and continuous infusions are not included in the SPC of levetiracetam, they may be an alternative that avoids the use of doses higher than 3000 mg. However, in patients with CrCl of 240 mL/min, it is not possible to reach the target plasma levels with the maximum authorized dose regardless of the mode of administration, and higher doses are compulsory.
For an adequate management of these patients, however, the ARC should be considered as a dynamic and temporary situation and, consequently, patients' renal function should be assessed daily to adjust dosing regimens if necessary [6, 16]. Equations that estimate glomerular filtration rate have been shown to be inappropriate in critically ill patients , and specifically in patients with ARC as they tend to underestimate the value of CrCl in this population . For this reason, creatinine clearance measured in urine should be the routine technique for calculating CrCl in ICU patients, and this value should be used to adjust the dosing regimens of drugs affected, such as levetiracetam.
Several factors are needed to be considered before considering applying in the clinical practice these results obtained by means of pharmacokinetic simulations, that is, the feasibility of the proposed dosage strategies must be pondered from different approaches. In the case of levetiracetam, there is sufficient experience to consider safe its administration in prolonged infusions [29,30,31,32,33,34]. However, it is important to take into account that extended infusions do not allow reaching therapeutic levels from the beginning of the treatment; therefore, in patients who were not undergoing previous treatment with the drug, it is necessary to consider a loading dose. Considering levetiracetam Vd is not affected by patient`s CrCl, the required loading dose would be the same as in patients without ARC (1000–1500 mg). On the other hand, it should be noted that the administration in extended or continuous infusion makes sense in situations in which we want to maintain stable drug levels in the blood for prolonged time. Therefore, these strategies would not be suitable for example in the acute treatment of status epilepticus, where high single dose bolus is usually recommended (1 to 3 g at a rate of 2 to 5 mg/kg/min or 40 to 60 mg/kg as a single dose infused over 5–15 min in combination with a parenteral benzodiazepine, and with a maximum dose of 4.5 g) . Finally, one potential drawback to prolonged or continuous infusion is the need for a venous access site in patients with limited lumens available.
The safety of administering doses higher than those authorized in the SPC must be considered. Our dosing simulations suggest the need to administer up to 6000 mg of levetiracetam daily to reach the target plasma level. To date, available evidence shows a good safety profile with the use of high doses of levetiracetam . Nevertheless, the objective of our simulations is to reach levels within the therapeutic range in a group of patients in which, due to their characteristics, the clearance of the drug is increased. For this reason, the use of high doses in this context can be considered safe, although it is necessary to closely monitor patients and, if possible, perform therapeutic monitoring of the drug.
Finally, when administering a drug in extended or continuous infusion, the information on drug stability is critical. Indeed, short post-dilution stability can prevent the drug from being administered in this way. However, different stabilities have been set for levetiracetam by different regulatory agencies, which can condition the proposal of new dosage regimens. On the one hand, EMA  accepted that levetiracetam is stable for at least 24 h at room temperature; on the other hand, FDA  limited it to 4 h. This discrepancy might suppose the use of extended and prolonged perfusions impossible under FDA criteria, whereas feasible in Europe. Therefore, it would be desirable to re-examinate the current recommendations about drug stability and to achieve an international consensus regarding this issue.
Although this research reached its aims, it has certain limitation: first of all, there is a limited number of PPK studies of levetiracetam including ARC condition and all the results are obtained from simulations based on a previously published study carried out in a relatively small population, which included patients with CrCL > 50 mL/min, but only 37% had ARC. Second, the objective of our simulations was to evaluate the adequacy of currently levetiracetam dosage regimens to achieve plasma levels within the range established by the ILAE. However, there is a lack of consensus about which the target concentrations for levetiracetam treatment are, and no specific target has been defined in prophylactic use. Although, the dosage regimens used in prophylactic context are usually the same as those listed for seizure treatment and the majority of clinical trials in which the efficacy of levetiracetam in prophylaxis has been evaluated use same guidelines, the relationship between levetiracetam plasma levels and its efficacy or toxicity needs to be further characterized in both situations. That is, even if there are studies that analyze the influence of the ARC in the achievement of plasma levels within the currently accepted range, there is no data linking this situation with higher incidence of seizures. Therefore, further investigations overcoming these limitations are needed to confirm these results in the clinical setting.