Population pharmacokinetics of polymyxin B in critically ill patients receiving continuous venovenous haemofiltration.

• Data on polymyxin B pharmacokinetics (PK) in patients undergoing continuous renal replacement therapy are very limited. • Population PK models were performed with 53 patients undergoing continuous venovenous haemofiltration (CVVH). • Clearance of polymyxin B was higher among patients on CCVH compared with patients off CVVH, accounting for 65% of total polymyxin B clearance. • A loading dose of polymyxin B 200 mg plus a fixed maintenance dose of 150 mg q12h for patients on CVVH would be an optimal regimen. Antibiotic dosing in critically ill patients undergoing continuous renal replacement therapy is considered challenging. This study aimed to analyse the population pharmacokinetics of polymyxin B in patients receiving continuous venovenous haemofiltration (CVVH), and to optimize individual dosing regimens in specific clinical scenarios. Patients treated with CVVH and polymyxin B for multi-drug-resistant Gram-negative bacterial infections were enrolled from two hospitals. Blood samples were collected during and outside CVVH, and assayed using a validated ultra-performance liquid chromatography-tandem mass spectrometry method. Population pharmacokinetic analysis and Monte Carlo simulations were performed using Phoenix NLME software. In total, 53 patients were included. The area under the concentration curve across 24 hours at steady state (AUC ss,24h) of polymyxin B during CVVH was 27.94 ± 10.92 mg‧h/L, which was significantly lower than that outside CVVH (77.89 ± 35.66 mg‧h/L) (P =1.65 × 10−8). The population pharmacokinetic model revealed that CVVH significantly increased the clearance of polymyxin B. Monte Carlo simulations showed that for patients on CVVH, a loading dose of 200 mg plus a fixed maintenance dose of 150 mg every 12 h had a high probability of achieving AUC ss,24h of 50–100 mg•h/L and the pharmacokinetic/pharmacodynamic target with a minimum inhibitory concentration ≤0.5 mg/L. For patients undergoing CVVH, high doses of polymyxin B and a dose-adjustment regimen based on therapeutic drug monitoring should be considered to improve efficacy. [ABSTRACT FROM AUTHOR]