Population Pharmacokinetics of Intravenous Levetiracetam in Neurosurgical Patients: Dosage Optimization Based on CrCl and Mannitol Use.

OBJECTIVE

Conventional low-dose levetiracetam (LEV) for post-neurosurgical seizure prophylaxis often yields subtherapeutic serum levels. This study characterized the population pharmacokinetics (PPK) of intravenous LEV to optimize dosing in neurosurgical patients.

METHODS

We conducted a retrospective PPK analysis in 87 neurosurgical patients (131 concentrations). Nonlinear mixed-effects modeling was used. Monte Carlo simulations identified regimens achieving ≥ 90% probability of target attainment (PTA) for trough concentrations (Cmin) of 12-46 μg/mL.

RESULTS

LEV median daily dose was 15.4 (7.7-43.5) mg/kg. A median of 1.5 (1-6) concentration samples were collected per patient. The LEV concentrations was 9.11 (1.39-33.79) μg/mL. Importantly, 78 random concentrations and Cmin of 10 patients were all subtherapeutic. Seizures occurred in 13 patients (14.9%); all responded to dose escalation/valproate. A one-compartment model described PK. Estimated clearance (CL) and volume of distribution were 3.73 L/h and 28.10 L, respectively. Covariate analysis identified CrCl and mannitol coadministration as significant CL determinants. Monte Carlo simulations indicated that without mannitol, 1 g q8h (0.5h infusion for CrCl at 20-89 mL/min; 4h infusion for CrCl at 90-129 mL/min) or 1.5 g q8h (0.5h infusion for CrCl at 130-180 mL/min) achieved > 90% PTA. With mannitol, higher doses were required: 1 g q8h (4h infusion, CrCl at 20-49 mL/min) or 1.5 g q8h (0.5h infusion for CrCl at 50-89 mL/min; 4h infusion for CrCl at 90-180 mL/min).

CONCLUSION

Standard LEV prophylaxis dosing often yields inadequate exposure in neurosurgical patients. LEV clearance is influenced by CrCl and mannitol use, higher doses is required for patients with concurrent mannitol therapy.