A Prospective, Real-World, Clinical Pharmacokinetic Study to Inform Lacosamide Dosing in Critically Ill Patients Undergoing Continuous Venovenous Hemofiltration (PADRE-02).

Aim Although the use of continuous renal replacement therapy (CRRT) has increased, limited dosing information exist on the effect of CRRT on antiepileptic drug pharmacokinetics. The objectives of this practice-based study are to evaluate the pharmacokinetics of lacosamide and recommend individualized dosing recommendations in critically ill patients receiving continuous venovenous hemofiltration (CVVH). Methods Seven patients receiving lacosamide and CVVH in a neurocritical care unit were enrolled. Pre-filter, post-filter, and ultrafiltrate samples were obtained at baseline, right after the completion of the infusion, and up to six additional sampling timepoints post-administration. Patient-specific flow rates and clinical measures were also simultaneously collected at the time of sampling. Plasma concentrations were measured using a validated HPLC-UV bioanalytical method. Non-compartmental analysis was utilized to characterize the pharmacokinetics of lacosamide. Results The observed mean sieving coefficient for lacosamide was 0.80 ± 0.10, suggesting high removal of lacosamide. Concentrations measured in six out of seven patients were observed to be outside the therapeutic range (5-12 mg/L). The estimated average volume of distribution was found to be similar to healthy patients (0.58 L/kg). The mean bias and precision of the estimated total clearance was -2.53% and 14.9%, respectively. Simulations of various doses suggest that effluent flow rate-based dosing regimens could be used to individualize lacosamide therapeutics. Conclusions CVVH clearance contributed a major fraction of the total lacosamide clearance in neurocritically ill patients. Given that drug clearance increases with higher effluent flow rates, lacosamide dosing regimens should be increased to match exposures observed in patients with normal renal function.