Ex vivo characterisation of effects of renal replacement therapy modalities and settings on pharmacokinetics of meropenem and vaborbactam [PublishAheadOfPrint]

The combination product meropenem/vaborbactam, with activity against KPC-producing carbapenem resistant Enterobacteriaceae, is likely to be used during renal replacement therapy. The aim of this work was to describe the extracorporeal removal (adsorption and clearance) of meropenem/vaborbactam during continuous venovenous hemofiltration (CVVH). An ex vivo model was used to examine the effects of a matrix of operational settings. Vaborbactam did not adsorb to AN69 (acrylonitrile and sodium-methallylsulfonate copolymer) ST100 (surface area, 1m²) hemofilter; whilst mean (± SD) meropenem adsorption was 9% (± 1%). The mean (± SD) sieving coefficients with AN69 ST100 and ST150 (surface area, 1.5m²) filters ranged from 0.97 ± 0.16 to 1.14 ± 0.12 and from 1.13 ± 0.01 to 1.53 ± 0.28, respectively, for meropenem; and for vaborbactam from 0.64 ± 0.39 to 0.90 ± 0.14 and 0.78 ± 0.18 to 1.04 ± 0.28, respectively. At identical settings, vaborbactam sieving coefficients were 25% to 30% lower than that of meropenem. Points of dilution, blood flow rates or effluent flow rates did not affect sieving coefficients for either drug. However, doubling the effluent flow rate resulted in > 50 to 100% increase in filter clearance for both drugs. Post-filter dilution resulted in 40 to 80% increase in filter clearance at high effluent flow rate (4000mL/h) compared with ~15% increase at low effluent flow rate (1000mL/h) for both drugs. For all combinations of setting and filters tested, vaborbactam clearance was lower than that of meropenem by ~20 to 40 %. Overall, meropenem/vaborbactam is efficiently cleared in CVVH mode.

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