Population Pharmacokinetic Modeling of Unbound Meropenem in Patients Undergoing Continuous Renal Replacement Therapy: An Observational Cohort Study

Background: The most effective dosing strategy of meropenem for patients undergoing continuous renal replacement therapy (CRRT) remains uncertain. This study aimed to analyze the population pharmacokinetics (popPKs) of unbound meropenem and establish an appropriate dosing approach. Methods: This prospective study involved 19 patients for the development of a popPK model and an additional 10 for its validation. Ethical approval was obtained. Results: The clearance of unbound meropenem was influenced by the sequential organ failure assessment (SOFA) score [=2.22 × (SOFA score/12)^1.88] and the effluent flow rate from the CRRT device, with an interindividual variability of 44.5%. The volume of distribution was affected by the simplified acute physiology score II [=23.1 × (simplified acute physiology score II/52)^1.54]. Monte Carlo simulations suggested meropenem doses ranging from 1.0 to 3.0 g/d using continuous infusion to achieve a target time above the 4 times of minimum inhibitory concentration of the unbound form (% f T >4×MIC ) of 100% for definitive therapy. For empirical therapy, a dose of 1.0 g/d using continuous infusion was recommended to target % f T >MIC of 100%. Conclusions: This study developed a popPK model for unbound meropenem in patients undergoing CRRT and formulated dosing guidelines. Clinical trial registration: UMIN000024321.