Three methods to optimise polymyxin B dosing using estimated AUC after first dose: validation with the data generated by Monte Carlo simulation.

Abstract

To achieve the AUC-guided dosing, we proposed three methods to estimate polymyxin B AUC across 24 h at steady state (AUC_SS,24h) using limited concentrations after its first dose.Monte Carlo simulation based on a well-established population PK model was performed to generate the PK profiles of 1000 patients with normal or abnormal renal function. Polymyxin B AUC_SS,24h was estimated for each subject using three methods (two-point PK approach, three-point PK approach, and four-point PK approach) based on limited concentration data in its first dose and compared with the actual AUC at steady state calculated using the linear-trapezoidal formula.In patients with normal renal function, the mean bias of two-point PK approach, three-point PK approach, and four-point PK approach was -8.73%, 1.37%, and -0.48%, respectively. The corresponding value was -11.15%, 1.99%, and -0.28% in patients with renal impairment, respectively. The largest mean bias of two-point PK approach, three-point PK approach, and four-point PK approach was -12.63%, -6.47%, and -0.54% when the sampling time shifted.The Excel calculators designed based on the three methods can be potentially used to optimise the dosing regimen of polymyxin B in the clinic.