Ex vivo assessment and simulation to guide cefepime-taniborbactam dosing recommendations for patients receiving...

Cefepime-taniborbactam dosing in patients undergoing continuous renal replacement therapy (CRRT) is unknown. We employed an ex vivo CRRT model to characterize transmembrane clearance (CL_TM) and derive optimal dosing regimens for patients supported by CRRT. CL_TM was determined in CVVH and CVVHD modes using the Prismaflex ST150 and HF1400 hemofilter sets. Samples were collected over 60 minutes to determine cefepime and taniborbactam concentrations at increasing effluent flow rates (ER). Sieving (SC) and saturation (SA) coefficients were measured and used to calculate CL_TM. Multiple linear regression determined cefepime and taniborbactam CL_TM as a function of ER, hemofilter, and mode. An established population pharmacokinetic model was integrated with the CL_TM, and a 1,000 patient Monte Carlo Simulation was conducted to determine exposures of potential dosing regimens for pneumonia. The overall mean ± SD SC/SA across CRRT modes, hemofilters, and ERs were 1.13 ± 0.08 and 1.03 ± 0.07 for cefepime and taniborbactam, respectively. ER was the primary driver (P < 0.001) of CL_TM for both drugs. For ER <3.5 L/h, cefepime and taniborbactam 1 g-0.25g q8h and 2 g-0.5g q12h as 4 h infusions achieved high probability of pharmacodynamic target attainment while keeping area under the curve exposures consistent with the proposed dose in pneumonia in non-CRRT patients. For ER ≥3.5 L/h, the optimum regimen was cefepime and taniborbactam 2 g-0.5 g q8h as a 4 h infusion. When incorporated into a population pharmacokinetic model, these CL_TM data were used to propose dosing recommendations for cefepime and taniborbactam as a function of ER in patients undergoing CRRT.