Composition of colistin

Colistin is produced by fermentation and consists of a mixture of at least 30 polymyxins that are closely related decapeptides. The active ingredients are further modified by chemical processes to produce the drug product colistimethate (CMS). The principal subcomponents colistin A and colistin B differ in their fatty acid and amino acid composition. The potential impact of the variations in subcomponent content on colistin pharmacokinetics, toxicity, bacteriological and clinical outcome, and resistance development still need to be elucidated (AJ Brink et al 2013).

In comparison with synthetic processes, manufacture by fermentation is more difficult to control, thus it can lead to the formation of more variable antibiotic products with more complex and less predictable composition and impurity. In Europe only one producer delivers the active ingredient colistin or the pharmaceutical drug product CMS. Therefore, the high variability among producers worldwide is not an issue in Europe but still does not prevent the batch-to-batch variability and thus, potential variability in pharmacokinetic profiles.

The European pharmacopoeia as well as other monographs for CMS do not define the limits for the different colistin subcomponents. This problem was presented at the recent Prato Meeting and is also recognised by the European Commission. EMA has been requested to give an opinion on whether the current control methods for CMS and colistin are appropriate and in line with the state of the art or whether the pharmacopoeial standards should be re-evaluated.

Worldwide, there are at least four commercially available parenteral products of CMS available that may vary in their chemical composition and thus, pharmacokinetic characteristics.

Mean (± SD) plasma concentration–time profiles of (a) CMS and (b) formed colistin in rats (n = 4) following an intravenous dose of CMS (28.1 mg/kg) (H.He et al 2013):

Colistin Pk rats

While all products had been standardized microbiologically in vitro, the exposure to formed colistin in vivo differed despite consistent CMS profiles. The results of this study has significant implications for the interpretation of pharmacokinetic, pharmacodynamic and toxicodynamic studies of CMS conducted in different parts of the world (H.He et al 2013).

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