Optimized meropenem dosage regimens using a pharmacokinetic/pharmacodynamic population approach in patients undergoing continuous venovenous haemodiafiltration with high-adsorbent membrane

Background The pharmacokinetics (PK) of antibiotics change during sepsis and continuous renal replacement therapies in critically ill patients. Limited evidence exists on the use of the oXiris((R)) high-adsorbent membrane. Objectives To develop a PK/pharmacodynamic (PD) model for meropenem in critically ill sepsis patients undergoing continuous venovenous haemodiafiltration (CVVHDF) with the oXiris((R)) membrane, and to design an optimal dosing regimen assessed according to the PTA. Methods A prospective, open-label, observational PK trial was performed (EUDRACT 2011-005902-30). We conducted PK studies (plasma and ultrafiltrate) for at least 24h after concomitant administration of CVVHDF and meropenem 1g q8h. We constructed a PK model using the non-linear mixed-effects approach (NONMEM 7.3). We evaluated the suitability of different dosage regimens using Monte Carlo simulations and calculated the PTA as the percentage of subjects achieving a given percentage of time above the MIC (fT(>MIC)). Results The PK of meropenem was best captured by a two-open-compartment model with zero-order input kinetics and first-order elimination. Extracorporeal CL was 7.78L/h [relative standard error (RSE) 16.45L/h] and central compartment V (V-c) was 24.9L (RSE 13.73L). Simulations showed that, for susceptible Pseudomonas aeruginosa isolates (EUCAST MIC <= 2mg/L) and attainment of 100%fT(>MIC), 500mg q8h given as extended (EI) or continuous infusion (CI) would be sufficient. For a target of 100%fT(>4xMIC), CI of 3000mg q24h or 2000mg q8h administered as EI or CI would be required. Conclusions We have constructed a PK model of meropenem in sepsis patients undergoing CVVHDF using the oXiris((R)) membrane. This tool will support physicians when calculating the optimal initial dose.