Population Pharmacokinetics of Levetiracetam in Patients with Traumatic Brain Injury and Subarachnoid Hemorrhage Exhibiting Augmented Renal Clearance

Background and Objective Patients with severe trauma exhibit augmented renal clearance, which can alter the dosing requirement of renally eliminated drugs. This study aimed to develop a population pharmacokinetic model for levetiracetam in patients with severe traumatic brain injury and aneurysmal subarachnoid hemorrhage, and use it to describe optimal dosing regimens. Methods This was a prospective open-label observational study. Critically ill adult patients with severe traumatic brain injury or aneurysmal subarachnoid hemorrhage without renal dysfunction and receiving levetiracetam were eligible. Serial levetiracetam plasma concentrations were analyzed to develop a population pharmacokinetic model and perform dosing simulations. Results A two-compartment model best described the concentration-time data from 30 patients. The mean +/- standard deviation parameter estimates were bioavailability (F) of 0.8 +/- 0.2, absorption rate constant of 2.4 +/- 2 h(-1), clearance 2.5 +/- 1.1 L/h, central volume of distribution 8.9 +/- 3.0 L/h, and transfer rate constraints of 1.8 +/- 1.1 h(-1) from central to peripheral compartments and 0.7 +/- 0.3 h(-1) from peripheral to central compartments. For the simulated intermittent dosing regimens, on average, the median trough concentration reduced by 50% for every 40-mL/min/1.73 m(2) increase in urinary creatinine clearance. Simulated doses of at least 6 g/day were required for some levels of augmented renal clearance. Conclusions Patients with severe traumatic brain injury and aneurysmal subarachnoid hemorrhage with augmented renal clearance are at risk of not achieving target levetiracetam plasma concentrations. We suggest dose titration guided by measured creatinine clearance, and/or, therapeutic drug monitoring if available, to minimize the risk of seizures.

Automated summary

A population pharmacokinetic model for levetiracetam was developed for patients with severe traumatic brain injury and aneurysmal subarachnoid hemorrhage to optimize dosing regimens. The study found that patients with augmented renal clearance may require higher doses of levetiracetam to achieve target plasma concentrations, suggesting dose adjustments based on creatinine clearance measurements or therapeutic drug monitoring to minimize seizure risk.