Aerosol Therapy with Colistin Methanesulfonate: a Biopharmaceutical Issue Illustrated in Rats

Abstract

The aim of this study was to evaluate the biopharmaceutical behavior of colistin methanesulfonate (CMS) with special focus on colistin presystemic formation after CMS nebulization in rats. CMS was administered (15 mg ⅐ kg ؊1 of body weight) either intravenously for systemic pharmacokinetic studies (n ‫؍‬ 6) or as an intratracheal nebulization for systemic pharmacokinetic studies (n ‫؍‬ 5) or for CMS and colistin concentration measurements in epithelial lining fluid (ELF) at 30, 120, and 240 min after nebulization (n ‫؍‬ 14). CMS and colistin concentrations were determined by a new liquid chromatography (LC)-tandem mass spectrometry (MS/MS) assay. Pharmacokinetic parameters were estimated by noncompartmental analysis. CMS and colistin pharmacokinetic data were consistent with previously published values when comparisons were possible. The fraction of the CMS dose converted systematically into colistin after intravenous CMS administration was estimated to be 12.5% on average. After CMS nebulization it was estimated that about two-thirds of the dose was directly absorbed within the systemic circulation, whereas one-third was first converted into active colistin, which was eventually absorbed. As a consequence, the colistin area under curve (AUC) reflecting systemic availability was about 4-fold greater after CMS intratracheal nebulization (607 ؎ 240 g ⅐ min ⅐ ml ؊1 ) than after CMS intravenous administration (160 ؎ 20 g ⅐ min ⅐ ml ؊1 ). CMS concentrations in ELF at 30 min and 120 min postnebulization were very high (in the order of several mg/ml) due to the limited volume of ELF but were considerably reduced at 240 min. Although lower (15% ؎ 5% at 120 min) in relative terms, colistin concentrations in ELF could be high enough for being active against microorganisms following CMS nebulization.

Pulmonary and Systemic Pharmacokinetics of Inhaled and Intravenous Colistin Methanesulfonate in Cystic Fibrosis Patients: Targeting Advantage of Inhalational Administration

“…Following the nebulization of sodium CMS (15 mg/kg of body weight) in rats, a ϳ4-fold-higher plasma concentration-versus-time exposure was observed for formed colistin compared to i.v. administration of the same CMS dose (39). We recently reported similar observations in rats where the intratracheal method resulted in formed colistin exposure in ELF that was 8,000-fold higher than that in plasma after i.v.…”

“…In contrast to the low systemic availability of CMS and formed colistin (Ͻ2 to 3% of the nebulized CMS dose recovered in urine) observed in CF subjects in the current study, Marchand et al (39) reported that the total dose of CMS administered by intratracheal nebulization to rats was absorbed into the systemic circulation either as CMS (systemic availability of ϳ70%) or following CMS conversion to colistin in the lungs (39% of the nebulized CMS dose). Following the nebulization of sodium CMS (15 mg/kg of body weight) in rats, a ϳ4-fold-higher plasma concentration-versus-time exposure was observed for formed colistin compared to i.v.…”

“…The fraction of the CMS dose that was converted to colistin following i.v. delivery in rats was ϳ13%, which suggests that following nebulization, the absorption of presystemically formed colistin contributes significantly to the systemic exposure of colistin (39). Such species differences (i.e., between rats and humans) can be attributed to the efficiency of the different nebulizer devices in delivering the total dose into the lungs, the physiological size of the rat versus the human lung, and the healthy versus infected status of the lungs, which can influence the barriers for absorption and impact clearance mechanisms (i.e., mucocilliary clearance, uptake by macrophages, and coughing).…”

Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 3. Tobramycin

“…The intraday and interday variabilities in plasma and BAL fluid were determined at three concentrations with a precision and accuracy of Ͻ15%. Concentrations of urea in plasma and BAL fluid were measured as previously described (7). TOB concentrations in epithelial lining fluid (C ELF ) were derived from measured TOB concentrations in BAL fluid (C BAL ) after correction by urea dilution (7).…”

“…Concentrations of urea in plasma and BAL fluid were measured as previously described (7). TOB concentrations in epithelial lining fluid (C ELF ) were derived from measured TOB concentrations in BAL fluid (C BAL ) after correction by urea dilution (7). TOB concentrations in plasma and ELF versus time were simultaneously analyzed by a nonlinear mixed-effects method with S-ADAPT software (v 1.52), and the final structural PK model was derived from previous studies (2, 3).…”