Levetiracetam Dosing Optimization in Neurocritical Care Population: Neuro-ARC Study

BACKGROUND: Levetiracetam, a first-line antiseizure medication, is primarily eliminated through the kidneys, with approximately 66% renal elimination. Consequently, its pharmacokinetics are significantly influenced by kidney function. Augmented renal clearance (ARC), a condition characterized by renal hyperfiltration, is frequently observed in critical care settings and can profoundly impact the disposition of renally eliminated drugs such as levetiracetam. Our objectives were to characterize levetiracetam pharmacokinetics in neurocritical care patients, identify covariates significantly influencing drug clearance, and provide clinicians with optimal dosage recommendations in those with and without ARC.

METHODS: This was a multicenter, prospective, observational study involving patients admitted to the participating centers with life-threatening neurological illnesses. Each participant had up to four plasma samples collected, and the samples were analyzed using a validated high-performance liquid chromatography method. The creatinine clearance (CL CR) of enrolled participants was measured using the 8-h urine collection method (measured CL CR [mCL CR]). Population pharmacokinetic modeling was performed using Monolix software. Monte Carlo simulations were performed to explore various dosage strategies and to suggest optimal levetiracetam regimens.

RESULTS: Our study included 50 patients, with 35 patients (70%) experiencing ARC. Trough levetiracetam levels were significantly lower in the ARC group compared with the no-ARC group (median [interquartile range] 4.4 [11.5] vs. 11.8 [19] mg/L, p value = 0.039, respectively). Population pharmacokinetic modeling showed levetiracetam clearance at 4.6 ± 2.97 L/h and volume of distribution at 0.56 ± 0.63 L/kg, following a one-compartment model. The mCL CR significantly affected levetiracetam clearance. Simulations indicated that an initial 500 mg twice daily (BID) dosage is insufficient. Patients with mCL CR  ≥ 90 mL/min/1.73 m 2, including patients with ARC, may need at least 1500 mg BID, whereas those with mCL CR 60-89 mL/min/1.73 m 2 may require an initial dosage of 1250 mg BID.

CONCLUSIONS: Augmented renal clearance significantly impacts the pharmacokinetics of levetiracetam by enhancing clearance. Dosing simulations revealed the inadequacy of the initial 500 mg BID regimen, indicating a minimum dosage of 1500 mg BID is necessary for patients experiencing ARC to achieve reference range concentrations.