Augmented Renal Clearance in Patients with Traumatic Brain Injury Impacts Levetiracetam

Abstract BACKGROUND: The purpose of this study was to compare serum concentrations of levetiracetam in patients with acute traumatic brain injury (TBI) during the first seven days following ICU admission. The hypothesis was levetiracetam concentrations are significantly lower in TBI patients with augmented renal clearance (ARC) compared to those with normal renal clearance.METHODS: This is a prospective cohort pharmacokinetic study of adults with moderate to severe TBI treated with levetiracetam during the first week after injury. Serial blood and urine collections were performed daily for analysis of levetiracetam, cystatin C, and creatinine clearance (CrCl) determinations. Patients were divided into two cohorts with (CrCl ³170ml/min/1.73m2) and without ARC.RESULTS: Twenty-two patients with moderate to severe TBI were included. The population consisted primarily of young male patients with severe TBI (mean age 40 years old, 68% male, median admission GCS 4). Each received levetiracetam 1000mg IV every 12 hours for the study period. ARC was present in 77.3% of patients, with the mean creatinine clearance in patients with ARC 170ml/min/1.73m2. Levetiracetam concentrations were significantly lower in patients with ARC than in those without ARC. Mean levetiracetam serum concentrations were below the typical therapeutic range for all study days in patients with ARC (< 6mcg/ml). In patients without ARC, the serum concentrations were also below the expected range on all but two study days which were days 4 and 5. Four of the 22 (18.2%) patients exhibited seizure activity during the study period (two of these patients exhibited ARC). Cystatin C concentrations were significantly lower in patients with ARC, though the mean for all patients was within the typical normal range.CONCLUSIONS: ARC has a high prevalence in patients with moderate to severe TBI. Levetiracetam concentrations after standard dosing were low in all TBI patients, but significantly lower in patients with ARC. This study highlights the need to consider personalized drug dosing in TBI patients irrespective of the presence of ARC.Clinical Trial Registration: This study was registered at cliicaltrials.gov (NCT02437838) Registered on May 8, 2015, https://clinicaltrials.gov/ct2/show/NCT02437838