Development of a dosing nomogram for continuous-infusion meropenem in critically ill patients based on a validated population pharmacokinetic model

Abstract

Background: Optimal antibiotic exposure is a vital but challenging prerequisite for achieving clinical success in ICU patients. Objectives: To develop and externally validate a population pharmacokinetic model for continuous-infusion meropenem in critically ill patients and to establish a nomogram based on a routinely available marker of renal function. Methods: A population pharmacokinetic model was developed in NONMEMVR 7.3 based on steady-state meropenem concentrations (C SS ) collected during therapeutic drug monitoring. Different serum creatinine-based markers of renal function were compared for their influence on meropenemclearance (the Cockcroft-Gault creatinine clearance CL CRCG , the CL CR bedside estimate according to Jelliffe, the Chronic Kidney Disease Epidemiology Collaboration equation and the four-variable Modification of Diet in Renal Disease equation). After validation of the pharmacokinetic model with independent data, a dosing nomogram was developed, relating renal function to the daily doses required to achieve selected target concentrations (4/8/16 mg/L) in 90% of the patients. Probability of target attainment was determined for efficacy (C SS ≥8 mg/L) and potentially increased likelihood of adverse drug reactions (C SS > 32 mg/L). Results: In total, 433 plasma concentrations (3.20-48.0mg/L) from 195 patients (median/P 0.05 -P 0.95 at baseline: weight 77.0/55.0-114 kg, CL CRCG 63.0/19.6-168mL/min) were used formodel building.We found that CL CRCG best describedmeropenem clearance (CL=7.71 L/h, CL CRCG =80mL/min). The developedmodel was successfully validated with external data (n=171, 73 patients). According to the nomogram, daily doses of 910/1480/2050/2800/ 3940mg were required to reach a target C SS =8mg/L in 90%of patients with CL CRCG =20/50/80/120/180mL/min, respectively. A lowprobability of adverse drug reactions ( < 0.5%) was associatedwith these doses. Conclusions: A dosing nomogram was developed for continuous-infusion meropenem based on renal function in a critically ill population.