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 (AUCSS,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 AUCSS,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.