PKP-036 Linezolid dose optimisation using monte carlo simulation

Abstract

BackgroundThe pharmacokinetic/pharmacodynamic (PK/PD) index for the efficacy of linezolid is defined as the area under the plasma drug concentration-time curve (AUC24)/minimum inhibitory concentration (MIC).PurposeTo establish linezolid dosing regimen to achieve the expected PK/PD target using THE Monte Carlo simulation for successful therapy.Material and methodsThe pharmacokinetic parameters of linezolid were obtained from published studies. MIC data were collected of our centre for the years 2013 and 2014 for Staphylococcus aureus and coagulase negative staphylococcus (CNS) isolates. The pharmacokinetic parameters were defined as a log normal distribution in the Monte Carlo simulation, and in the case of MIC, a discrete distribution. A Monte Carlo simulation with 10 000 subjects was performed using the SimulAr program. Acumulative fraction of response (CFR) was calculated (CFR values of >90% represent an optimal regimen). Optimal AUC/MIC ≥100 was considered.ResultsAfter literature review, a population pharmacokinetic study of linezolid was selected in adult patients suffering from Gram positive bacterial infections. A one compartment PK model was used with a first order elimination process and the final equation model for Linezolid clearance (ClLin)=0.0258xCreatinine clearance (ClCr) (L/h)+2.03 with interindividual variability of 30.5%. ClCr was estimed using the Cockcroft and Gault method. MICs for S aureus were fixed at 0.5, 1, 2, 4 and 8 μl/mL, with a relative distribution of 0.0075, 0.3387, 0.4807, 0.1667 and 0.0064, respectively. For CNS, MICs were fixed at 0.5, 1, 2 and 4 μl/mL with a relative distribution of 0.3267, 0.6707, 0.0013 and 0.0013, respectively. The simulation analysis for S aureus suggested doses of 900, 1200, 1800 and 2400 mg/day for ClCr <25, 25–60, 60–125 and >125 mL/min, respectively. For CNS, doses of 600, 900 and 1200 mg/day were suggested for ClCr <60, 60–125 and >125 mL/min, respectively.ConclusionAccording to the population pharmacokinetic model and the MIC chosen, linezolid doses should be individualised based on patient ClCr and strain of staphylococcus spp isolated.References and/or AcknowledgementsMatsumoto, Shigemi A, Takeshita A, et al. Int J Antimicrob Agents 2014;44:242-7No conflict of interest.