Population pharmacokinetics and probability of target attainment in patients with sepsis under renal replacement therapy receiving continuous infusion of meropenem: sustained low-efficiency dialysis (SLED) and continuous veno-venous haemodialysis (CVVHD).

AIM To describe the population pharmacokinetics (popPK) and probability of target attainment (PTA) of continuous infusion (CI) of meropenem in septic patients receiving renal replacement therapy (RRT). METHODS Fiveteen patients without RRT, 13 patients receiving sustained low-efficiency dialysis (SLED) and 12 patients receiving continuous veno-venous haemodialysis (CVVHD) were included. PopPK analysis with Monte Carlo simulations for different dosing regimens was performed. For minimum inhibitory concentration (MIC) 2 mg/l was chosen. The target was set as 50% T ≥ 4x MIC . RESULTS The PK of meropenem was best described by a one-compartment model with linear elimination. Serum creatinine, residual diuresis and time on RRT, with no difference between SLED and CVVHD, were found to be significant covariates affecting clearance, explaining greater than 20% of the clearance between subject variability. PTA analysis showed that in patients with RRT, 2 g/24 h, meropenem CI achieved a PTA of 95%. In patients without RRT, the target was achieved with 3 g/24 h CI or prolonged infusion of 1 g meropenem over 8 hours but not with bolus application of 1 g meropenem for 8 hours. Only two patients (both without RRT) had meropenem concentrations below the target level. However, approximately half of the patients with RRT receiving CI 3 g/24 h meropenem had toxic concentrations. CONCLUSIONS We found relevant PK variability for meropenem CI in septic patients with or without RRT, leading to a substantial risk for overdosing in patients with RRT. This finding highlights the strong demand for personalized dosing in critically ill.