Development and Use of an Ex-Vivo In-Vivo Correlation to Predict Antiepileptic Drug Clearance in Patients Undergoing Continuous Renal Replacement Therapy.

Abstract

Results from previous ex-vivo continuous renal replacement therapy (CRRT) models have successfully demonstrated similar extraction coefficients (EC) identified from in-vivo clinical trials. The objectives of this study are to develop an ex-vivo in-vivo correlation (EVIVC) model to predict drug clearance for commonly used antiepileptics and to evaluate similarity in drug extraction across different CRRT modalities to extrapolate dosing recommendations. Levetiracetam, lacosamide, and phenytoin CRRT clearance was evaluated using the Prismaflex CRRT system and M150 hemodiafilters using an albumin containing normal saline (ALB-NS) vehicle with 3 different albumin concentrations (2g/dL, 3g/dL, and 4g/dL) and a human plasma vehicle at 3 different effluent flow rates (1 L/hr, 2 L/hr, and 3 L/hr). Blood and effluent/dialysate concentrations were collected after circuit priming. ECs were calculated for each drug, modality, vehicle, and experimental arm combination. The calculated average EC for levetiracetam and lacosamide was approximated to the fraction unbound from plasma protein. Human plasma and ALB-NS vehicles demonstrated adequate prediction of in-vivo CRRT clearance. Geometric mean ratios indicated similarity in extraction coefficients when comparing between hemofiltration and hemodiafiltration modalities and between filtration and dialysis modalities at effluent flow rates ≤ 2L/hr. Evaluation of phenytoin provided inconsistent findings with regards to extraction coefficient similarity across different CRRT modalities. The findings indicate that an ex-vivo study can be used as a surrogate to predict in-vivo levetiracetam and lacosamide clearance in patients receiving CRRT.