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Optimizing hollow-fiber-based pharmacokinetic assay via chemical stability study to account for inaccurate simulated drug clearance of rifampicin

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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.

Optimizing hollow-fiber-based pharmacokinetic assay

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References

  1. Peleg AY, Seifert H, Paterson DL (2008) Acinetobacter baumannii: emergence of a successful pathogen. Clin Microbiol Rev 21:538–582

    Article  CAS  Google Scholar 

  2. Talbot GH, Bradley J, Edwards JE, Gilbert D, Scheld M, Bartlett JG (2006) Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America. Clin Infect Dis 42:657–668

    Article  Google Scholar 

  3. Evans ME, Feola DJ, Rapp RP (1999) Polymyxin B sulfate and colistin: old antibiotics for emerging multiresistant gram-negative bacteria. Ann Pharmacother 33:960–967

    Article  CAS  Google Scholar 

  4. Li J, Rayner CR, Nation RL, Owen RJ, Spelman D, Tan KE, Liolios L (2006) Heteroresistance to colistin in multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother 50:2946–2950

    Article  CAS  Google Scholar 

  5. Rahal JJ (2006) Novel antibiotic combinations against infections with almost completely resistant Pseudomonas aeruginosa and Acinetobacter species. Clin Infect Dis 43(Supplement 2):S95–S99

    Article  CAS  Google Scholar 

  6. Lim TP, Tan TY, Lee W, Suranthran S, Tan TT, Hsu LY, Kwa AL (2009) In vitro activity of various combinations of antimicrobials against carbapenem-resistant Acinetobacter species in Singapore. J Antibiot (Tokyo) 62:675–679

    Article  CAS  Google Scholar 

  7. Zavascki AP, Goldani LZ, Li J, Nation RL (2007) Polymyxin B for the treatment of multidrug-resistant pathogens: a critical review. J Antimicrob Chemother 60:1206–1215

    Article  CAS  Google Scholar 

  8. Orwa JA, Govaerts C, Busson R, Roets E, Van Schepdael A, Hoogmartens J (2001) Isolation and structural characterization of polymyxin B components. J Chromatogr A 912:369–373

    Article  CAS  Google Scholar 

  9. Govaerts C, Orwa J, Van Schepdael A, Roets E, Hoogmartens J (2002) Characterization of polypeptide antibiotics of the polymyxin series by liquid chromatography electrospray ionization ion trap tandem mass spectrometry. J Pept Sci 8:45–55

    Article  CAS  Google Scholar 

  10. Gumbo T, Louie A, Deziel MR, Liu W, Parsons LM, Salfinger M, Drusano GL (2007) Concentration-dependent Mycobacterium tuberculosis killing and prevention of resistance by rifampin. Antimicrob Agents Chemother 51:3781–3788

    Article  CAS  Google Scholar 

  11. Zavascki AP, Goldani LZ, Cao G, Superti SV, Lutz L, Barta AL, Ramos F, Boniatti MM, Nation RL, Li J (2008) Pharmacokinetics of intravenous polymyxin B in critically ill patients. Clin Infect Dis 47:1298–1304

    Article  CAS  Google Scholar 

  12. D’Argenio DZ, Schumitzky A (1997) ADAPT II user’s guide: pharmacokinetic pharmacodynamic systems analysis software. Biomedical simulations resource, University of Southern California, Los Angeles

  13. He J, Figueroa DA, Lim TP, Chow DS, Tam VH (2010) Stability of polymyxin B sulfate diluted in 0.9 % sodium chloride injection and stored at 4 or 25 degrees C. Am J Health Syst Pharm 67:1191–1194

    Article  CAS  Google Scholar 

  14. He J, Ledesma KR, Lam WY, Figueroa DA, Lim TP, Chow DS, Tam VH (2010) Variability of polymyxin B major components in commercial formulations. Int J Antimicrob Agents 35:308–310

    Article  CAS  Google Scholar 

  15. Kwa AL, Abdelraouf K, Low JG, Tam VH (2011) Pharmacokinetics of polymyxin B in a patient with renal insufficiency: a case report. Clin Infect Dis 52:1280–1281

    Article  Google Scholar 

  16. Govaerts C, Rozenski J, Orwa J, Roets E, Van Schepdael A, Hoogmartens J (2002) Mass spectrometric fragmentation of cyclic peptides belonging to the polymyxin and colistin antibiotics studied by ion trap and quadrupole/orthogonal-acceleration time-of-flight technology. Rapid Commun Mass Spectrom 16:823–833

    Article  CAS  Google Scholar 

  17. Tam VH, Cao H, Ledesma KR, Hu M (2011) In vitro potency of various polymyxin B components. Antimicrob Agents Chemother 55:4490–4491

    Article  CAS  Google Scholar 

  18. New LS, Saha S, Ong MM, Boelsterli UA, Chan EC (2007) Pharmacokinetic study of intraperitoneally administered troglitazone in mice using ultra-performance liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 21:982–988

    Article  CAS  Google Scholar 

  19. Balbão MS, Bertucci C, Bergamaschi MM, Queiroz RH, Malfará WR, Dreossi SA, de Paula ML, Queiroz ME (2010) Rifampicin determination in plasma by stir bar-sorptive extraction and liquid chromatography. J Pharm Biomed Anal 51:1078–1083

    Article  Google Scholar 

  20. Kenny MT, Strates B (1981) Metabolism and pharmacokinetics of the antibiotic rifampin. Drug Metab Rev 12:159–218

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported by the SingHealth Foundation Grant SHF/FG399P/2008 provided to T.P.L. and A.L.H.K. and the NUS Academic Research Fund (AcRF) Tier 1 Grant R-148-000-135-112 provided to E.C.Y.C.

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Author notes

  1. Lee Sun New

    Present address: MSD Translational Medicine Research Centre Singapore, 8 Biomedical Grove, #04-01/05, Neuros Building, Singapore, 138665, Singapore

  2. Jing Wen Oh

    Present address: Taiho Pharma Singapore Pte Ltd, 390 Havelock Road, #06-07, King’s Centre, Singapore, 169662, Singapore

Authors and Affiliations

  1. Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore

    Lee Sun New, Jing Wen Oh, Gavin Jia Sheng Cheah & Eric Chun Yong Chan

  2. Department of Pharmacy, Singapore General Hospital, Outram Road, Singapore, 169069, Singapore

    Tze Peng Lim & Andrea L. Kwa

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  1. Lee Sun New
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Correspondence to Eric Chun Yong Chan.

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New, L.S., Lim, T.P., Oh, J.W. et al. Optimizing hollow-fiber-based pharmacokinetic assay via chemical stability study to account for inaccurate simulated drug clearance of rifampicin. Anal Bioanal Chem 405, 1407–1415 (2013). https://doi.org/10.1007/s00216-012-6549-7

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  • DOI: https://doi.org/10.1007/s00216-012-6549-7

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