Population pharmacokinetic modelling of total and unbound flucloxacillin in non-critically ill patients to devise a rational continuous dosing regimen

Objective This study's objective was to describe the population pharmacokinetics of total and unbound flucloxacillin in non-critically ill patients, and to devise a rational continuous dosing regimen for this population. Methods Total and unbound flucloxacillin pharmacokinetics in 30 non-critically ill patients receiving intravenous flucloxacillin were analysed using non-linear mixed-effects modelling. Monte Carlo simulation was used to assess the fraction of the population reaching effective unbound flucloxacillin levels and the fraction reaching potential neurotoxic exposure for various continuous dosing regimens. Results The observed protein binding varied between 64.6–97.1%. The unbound fraction was significantly associated with serum albumin and was concentration-dependent. The parameter estimates of the final model were: Cltotal 122 L/h, Clrenal 1.41 L/h, Vc 190 L, Vp 33.9 L, Q 16.8 L/h, Kd 9.63 mg/L, θBmax 177 mg/L,θalb 0.054. A continuous dose of 6 g/24 hours was sufficient for 100% of the population to obtain a unbound concentration of > 0.25 mg/L. With 14 g/24 h, 91.2% of the population was predicted to reach concentrations of > 2 mg/L, the clinical breakpoint for Staphylococcus aureus. Potential toxic unbound flucloxacillin levels were reached in 2.0% of the population with 6 g/24 h, and 24.1% with 14 g/24 h. Conclusions This study showed that a continuous infusion of 6 g/24 h flucloxacillin is sufficient to treat most infections in non-critically ill patients. With this dosing regimen, an unbound serum concentration flucloxacillin > 0.25 mg/L was reached in 100% of the patients, with minimal chance of neurotoxicity.