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Title: Optimizing hollow-fiber-based pharmacokinetic assay via chemical stability study to account for inaccurate simulated drug clearance of rifampicin
Authors: New, L.S. 
Lim, T.P.
Oh, J.W.
Cheah, G.J.S.
Kwa, A.L.
Chan, E.C.Y. 
Keywords: Clearance
Hollow-fiber infection model
Multidrug-resistant bacteria
Polymyxin B
Issue Date: 2013
Citation: New, L.S., Lim, T.P., Oh, J.W., Cheah, G.J.S., Kwa, A.L., Chan, E.C.Y. (2013). Optimizing hollow-fiber-based pharmacokinetic assay via chemical stability study to account for inaccurate simulated drug clearance of rifampicin. Analytical and Bioanalytical Chemistry 405 (4) : 1407-1415. ScholarBank@NUS Repository.
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. © 2012 Springer-Verlag Berlin Heidelberg.
Source Title: Analytical and Bioanalytical Chemistry
ISSN: 16182642
DOI: 10.1007/s00216-012-6549-7
Appears in Collections:Staff Publications

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