Aerosol therapy with colistin: a biopharmaceutical concern as illustrated in rats
Abstract number: P1603
Marchand S., Thi Viet Phuong D., Gobin P., Olivier J., Mimoz O., Couet W.
Objective: The aim of this study was to investigate the pharmacokinetics of colistin methanesulphonate (CMS) and colistin following CMS nebulisation in rats.
Methods: Male rats (280320g) received (i) a CMS dose of 15 mg·kg-1 either as an intravenous (IV) bolus (n = 6) or (ii) by nebulisation using a MicroSprayer IA-1B® system (Penn Century Inc, Philadelphia, US) (n = 6), or (iii) colistin subcutaneously (SC) at a dose of 1.5 mg·kg-1. Multiple blood samples were drawn from a catheter implanted the day before through anaesthesia in a femoral artery, for up to 300 min. CMS and colistin plasma concentrations were determined by a new validated LC-MS/MS assay. Pharmacokinetics parameters were estimated using a non-compartmental analysis.
Results: Mean±SD concentrations of CMS and or colistin are illustrated below (TABLE).
Colistin clearance was estimated to 8.5±1.0 mL/min/kg after SC administration, assuming complete bioavailability and allowing to estimate that the fraction of CMS converted to colistin after CMS IV administration was only equal to 13% on average. It could then be estimated that after CMS nebulisation 69% of the dose reached directly the systemic circulation and that 30% was converted within the lung before being absorbed. Therefore colistin area under curve was higher after CMS nebulisation (486±170 mg·mL/min) than after IV administration of CMS at the same dose (160±20 mg·mL/min), meaning that colsitin exposure was 3 folds greater after nebulisation than IV administration of CMS.
Conclusion: Because colistin is nebulised as a prodrug (CMS), conversion to the active moiety within the lung is necessary to provide efficacy. Yet because systemic conversion of CMS into colistin is limited to 13% on average, and because colistin formed within lungs (30% of the dose) is eventually totally absorbed, colistin systemic exposure is greater after nebulisation and therefore toxicity may also be greater. Although this observation should not be directly extrapolated to humans, this issue deserves consideration.
|Session name:||Abstracts 20th European Congress of Clinical Microbiology and Infectious Diseases|
|Location:||Vienna, Austria, 10 - 13 April 2010|
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