Population Pharmacokinetic Model for Unbound Concentrations of Daptomycin in Patients with MRSA Including Patients Undergoing Hemodialysis

Background and Objective: Unbound daptomycin concentrations are responsible for pharmacologically beneficial and adverse effects, although most previous reports have been limited to the use of total concentrations. We developed a population pharmacokinetic model to predict both total and unbound daptomycin concentrations. Methods: Clinical data were collected from 58 patients with methicillin-resistant Staphylococcus aureus including patients undergoing hemodialysis. A total of 339 serum total and 329 unbound daptomycin concentrations were used for model construction. Results: Total and unbound daptomycin concentration was explained by a model that assumed first-order distribution with two compartments, and first-order elimination. Normal fat body mass was identified as covariates. Renal function was incorporated as a linear function of renal clearance and independent non-renal clearance. The unbound fraction was estimated to be 0.066 with a standard albumin of 45 g/L and standard creatinine clearance of 100 mL/min. Simulated unbound daptomycin concentration was compared with minimum inhibitory concentration as a measure of clinical effectiveness and exposure-level-related induction of creatine phosphokinase elevation. The recommended doses were 4 mg/kg for patients with severe renal function [creatinine clearance (CLcr) ≤ 30 mL/min] and 6 mg/kg for patients with mild to moderate renal function (CLcr > 30 and ≤ 60 mL/min). A simulation indicated that dose adjusted by body weight and renal function improved target attainment. Conclusions: This population pharmacokinetics model for unbound daptomycin could help clinicians to select the appropriate dose regimen for patients undergoing daptomycin treatment and reduce associated adverse effects.