title: Optimizing hollow-fiber-based pharmacokinetic assay via chemical stability study to account for inaccurate simulated drug clearance of rifampicin.
abstract: With increasing multidrug resistance coupled to a poor development pipeline, clinicians are exploring antimicrobial combinations to improve treatment outcomes. In vitro hollow-fiber infection model (HFIM) is employed to simulate human in vivo drug clearance and investigate pharmacodynamic synergism of antibiotics. Our overarching aim was to optimize the HFIM-based pharmacokinetic (PK) assay by using rifampicin and polymyxin B as probe drugs. An ultrapressure liquid chromatography tandem mass spectrometry method was validated for the quantification of rifampicin and polymyxin B components. In vitro profiling studies demonstrated that the experimental PK profiles of polymyxin B monotherapy were well correlated with the human population PK data while monotherapy with rifampicin failed to achieve the expected maximum plasma concentration. Chemical stability studies confirmed polymyxin B was stable in broth at 37 °C up to 12 h while rifampicin was unstable under the same conditions over 12 and 80 h. The calculated mean clearance of rifampicin due to chemical degradation was 0.098 ml/min accounting for 12.2 % of its clinical total clearance (CL = 0.8 ml/min) based on population PK data. Our novel finding reinforces the importance to optimize HFIM-based PK assay by performing chemical stability study so as to account for potential discrepancy between experimental and population PK profiles of antimicrobial agents.
authors.affiliation: Department of Pharmacy, National University of Singapore, Singapore, Singapore.
authors.forename: Lee Sun
authors.initials: LS
authors.lastname: New
authors.forename: Tze Peng
authors.initials: TP
authors.lastname: Lim
authors.forename: Jing Wen
authors.initials: JW
authors.lastname: Oh
authors.forename: Gavin Jia Sheng
authors.initials: GJ
authors.lastname: Cheah
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Kwa
authors.forename: Eric Chun Yong
authors.initials: EC
authors.lastname: Chan
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy; D040981:Acinetobacter baumannii / Q000187:drug effects / Q000254:growth & development; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D010600:Pharmacology / Q000295:instrumentation / Q000379:methods*; D011112:Polymyxin B / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012293:Rifampin / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D011112:Polymyxin B; D012293:Rifampin