Prediction of tissue exposures of polymyxin-B, amikacin and sulbactam using physiologically-based pharmacokinetic modeling

• DOI: 10.3389/fmicb.2024.1435906
• Publication Date: 2024-10-07T04:28:13Z
• Authors: Mengyuan Wu; Kun Feng; Xiao Wu; Chang Liu; Shixing Zhu; Frederico S. Martins; Mingming Yu; Zhihua Lv; Meixing Yan; Sherwin K. B. Sy
• Keywords: Amikacin; Sulbactam; Pharmacodynamics; Polymyxin B; Polymyxin

Background The combination antimicrobial therapy consisting of amikacin, polymyxin-B, and sulbactam demonstrated in vitro synergy against multi-drug resistant Acinetobacter baumannii . Objectives objectives were to predict drug disposition extrapolate their efficacy the blood, lung, heart, muscle skin tissues using a physiologically-based pharmacokinetic (PBPK) modeling approach evaluate achievement target pharmacodynamic (PD) indices A. Methods A PBPK model was initially developed for adult subjects, then scaled pediatrics, accounting both renal non-renal clearances. simulated plasma tissue exposures compared observed data from humans rats. Efficacy inferred joint probability attainment PD indices. Results adults pediatrics within 0.5 2 boundary mean fold error ratio between means. Simulated skin, heart consistent with reported penetration exposure. In virtual pediatric population <18 years age dosing regimens, interpretive breakpoints achieved 85–90% population. Conclusion utility simulate amount antibacterial exposure is practical overcome difficulty obtaining concentrations As therapy, amikacin/polymyxin-B/sulbactam exhibited sufficient combat extremely clinical isolates.