Linezolid dosing in critically ill patients undergoing various modalities of renal replacement therapy: a pooled population pharmacokinetic analysis

The altered pharmacokinetics (PK) of linezolid are pronounced in critically ill patients undergoing different modalities of renal replacement therapy (RRT). This study aimed to provide a pooled population PK analysis of linezolid in patients undergoing RRT, and to evaluate the pharmacodynamic target attainment of linezolid standard dosing (600 mg q12h). In total, 414 pooled linezolid concentration observations from 69 patients undergoing intermittent haemodialysis (IHD), sustained low-efficiency dialysis (SLED) or continuous RRT were used to develop the population PK model. The probability of target attainment (PTA) for the efficacy markers of 85% T>minimum inhibitory concentration (MIC) and area under the concentration–time curve (AUC)/MIC >100 was evaluated, and the risk of toxicity was estimated based on Cmin ≥10 mg/L. Linezolid concentration data were described adequately by a two-compartment model. Renal function and body weight were identified as significant modifiers for endogenous clearance of linezolid. Simulations demonstrated that the PTA of 85% T>MIC and AUC/MIC>100 was unacceptably low (0–58.6%, MIC ≥1 mg/L) in RRT patients with preserved renal function, while desirable 85% T>MIC attainment (≥ 90%, MIC ≤2 mg/L) was achieved in anuric RRT patients. The predicted risk of toxicity was negligible (<1.0%) in patients with preserved renal function (regardless of RRT modality), while the probability of reaching Cmin ≥10 mg/L was high (17.9–20.9%) for the anuric patient population undergoing IHD or SLED. In conclusion, standard linezolid dosing is adequate for anuric RRT patients with MIC ≤2 mg/L.