Pharmacokinetics and Optimal Dosing of Levetiracetam in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy (LEVCRRT)

Critically ill adult patients aged 18 years or older admitted to ICUs who receive levetiracetam during CRRT. Eligible participants must have received CRRT for at least 24 hours and meet the study's inclusion and exclusion criteria.

Levetiracetam administered as part of routine clinical care to critically ill adult patients receiving CRRT. The dose, dosing interval, and route of administration are determined by the treating physician. CRRT is prescribed and managed by the treating clinical team (nephrologist) as part of routine clinical care. The investigators do not assign or modify levetiracetam treatment or CRRT prescriptions for research purposes. Levetiracetam concentrations are measured in blood, CRRT effluent, and urine samples collected at protocol-specified time points to characterize its pharmacokinetic profile during CRRT.

Monte Carlo simulations based on the developed population pharmacokinetic model will be used to estimate the probability of target attainment (PTA) for each simulated levetiracetam dosing regimen. Target attainment will be evaluated according to the prespecified therapeutic concentration and AUC target criteria in the study protocol. Results will be reported as the probability or percentage of simulated patients achieving the target for each dosing regimen.

Levetiracetam AUC will be estimated using noncompartmental analysis of concentration-time data collected over a single dosing interval. Simultaneous samples will be collected from the pre-filter, post-filter, and effluent ports before dosing and at 7 prespecified time points after intravenous or oral administration.

The volume of distribution of levetiracetam will be estimated using noncompartmental pharmacokinetic analysis based on the administered dose, elimination rate constant, and AUC.

Total clearance of levetiracetam will be estimated using noncompartmental pharmacokinetic analysis based on the administered dose and AUC.

The sieving coefficient (SC) and saturation coefficient (SA) of levetiracetam will be determined using pre-filter, post-filter, and effluent concentrations to evaluate drug transfer across the CRRT filter under different CRRT modalities, including continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), and continuous venovenous hemodiafiltration (CVVHDF).

Levetiracetam clearance by CRRT will be calculated based on pre-filter, post-filter, and effluent concentrations, together with replacement or dialysate flow rates according to the CRRT modality and dilution method, including CVVH, CVVHD, and CVVHDF.

Renal clearance of levetiracetam will be calculated based on urinary levetiracetam concentrations, urine volume, and plasma levetiracetam concentrations.

Non-renal clearance of levetiracetam will be estimated from total systemic drug clearance after accounting for renal and CRRT clearance.

The typical population value of levetiracetam clearance will be estimated using nonlinear mixed-effects modeling based on pre-filter and post-filter plasma concentration data collected from critically ill patients receiving CRRT.

The typical population value of levetiracetam volume of distribution will be estimated using nonlinear mixed-effects modeling based on pre-filter and post-filter plasma concentration data collected from critically ill patients receiving CRRT.

The typical population value of CRRT-mediated levetiracetam clearance will be estimated using levetiracetam concentrations in plasma and effluent fluid, together with effluent flow rate, in critically ill patients receiving CRRT.