An ex vivo model to determine transmembrane clearance of antimicrobials during continuous renal replacement therapy

The extracorporeal removal of antibiotics in patients requiring continuous renal replacement therapy (CRRT) can be impacted by both individual drug properties as well as factors related to the dialysis prescription. Herein, we describe the detailed methodology for setting up an ex vivo CRRT model to determine the adsorption and transmembrane clearance (CLTM) of cefepime, meropenem, levofloxacin and micafungin across various haemofilters, modes and effluent flow rates.

Two methods to determine CLTM were evaluated to derive optimal dosing regimens and method development: CLSC/SA was calculated by the sieving coefficient (SC) for continuous veno-venous haemofiltration and saturation coefficient (SA) for continuous veno-venous haemodialysis. An alternative calculation CLNCM, was derived from non-compartmental analysis of concentrations from the central reservoir.

The average SC/SA of cefepime, meropenem, levofloxacin and micafungin were 1.01, 1.04, 0.87 and <0.01, respectively, which was concordant with their protein-binding profiles. Effluent rate was the primary driver of CLTM for all drugs except micafungin and could be used to guide proposed dosing regimens. CLSC/SA and CLNCM resulted in similar values for cefepime, meropenem and levofloxacin across the effluent rate range but were discordant for micafungin due to filter adsorption; thereby suggesting both methods could be utilized to evaluate CLTM provided negligible filter adsorption is observed.

These ex vivo methods can be combined with patient pharmacokinetic data to determine optimal drug dosing regimens for CRRT during new drug development.