PK of colistin

In vivo conversion of the prodrug colistimethate sodium (CMS)

The typical serum and urine concentration versus time profiles of colistin after parenteral administration shown in the product information are misleading due to the non-specificity of microbiological assays. Such assays are incapable of differentiating the colistin present in the biological sample at the time of collection from the colistin formed in vitro by hydrolysis of colistimethate during the microbiological assay (J. Li et al 2006).
Conversion of CMS generates a complex mixture of partially sulfomethylated derivatives and colistin, formation of the latter being a prerequisite for antibacterial activity. Only a low proportion (∼3 to 13%) of the i.v. dose of CMS is converted to colistin.

Colistin PK

In vitro conversion of CMS

When concentrations of colistin are being measured by HPLLC in biological fluids following the administration of CMS, the hydrolysis of CMS to colistin during sample storage and preparation for analysis should be minimized to avoid falsely elevated values (J Li et al 2003).

Levels of colistin in samples of CMS in water kept at 37°C, expressed as a percentage of the original CMS on a molar basis (J Li et al 2003).

Colistin-CMS in vitro

 

Colistin serum concentrations

Recent population PK studies in critically ill patients have revealed that plasma concentrations of colistin, the active antibacterial formed by hydrolysis of CMS in the body, will increase slowly (over a day or longer) after the first dose in a maintenance dosing regimen. This highlights the importance of initiating therapy with a loading dose of CMS, and this now implemented in some clinical studies but not universally.

Model-predicted concentrations of formed colistin in a typical patient following the use of the current dosing regimen (3 MU as a 15-min infusion of CMS every 8 h [q8h]) and alternative dosing regimens with loading doses of 9 or 12 MU CMS as infusions of 15 min or 2 h and a maintenance dose of 4.5 MU CMS every 12 h (q12h) (Plachouras et al 2009):

Colistin serum conc

Colistin urine concentrations

Intracellular tubular concentrations

Colistin tissue concentrations

Colistin is a hydrophilic molecule and little pharmacokinetic information beyond serum concentrations exist. Based on a relatively small Vd it could be assumed that colistin distributes mainly in the interstitial fluid of tissues, thus in the extracellular compartment.

ELF

In rats, the conversion of CMS to colistin in ELF is higher than the corresponding fractional conversion in plasma after i.v. administration (SW Yapa et al, 2013).CMS conversion in ELF

IT= intratracheal, IV= intravenous

 

 

 

 

Protein binding

The unbound fraction of colistin A is concentration dependent whereas the unbound fraction of colistin B is constant (average of 43%) across the evaluated concentrations from the plasma of healthy volunteers. Consequently the unbound fraction of colistin A+B is dependent on the ratio of colistin A and colistin B. The predicted unbound fraction is 15% for colistin A + B of 0.01 mg/L and 34% for 2.5 mg/L. Binding to AAG does not seem to play a big role in humans.
Unbound fraction of colistin A and colistin B in healthy volunteers (left), and total colistin in healthy volunteers and patients (right) (A F Syed Mohamed, 2013):

Colistin proteinbinding human

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