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Substantial Targeting Advantage Achieved by Pulmonary Administration of Colistin Methanesulfonate in a Large-Animal
Cornelia B Landersdorfer1,2,3, Tri-Hung Nguyen4, Linh Thuy Lieu4
1Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia cornelia.landersdorfer@monash.edu michelle.mcintosh@monash.edu.
Abstract:
Colistin, administered as its inactive prodrug colistin methanesulfonate (CMS), is often used in multidrug-resistant Gram-negative pulmonary infections. The CMS and colistin pharmacokinetics in plasma and epithelial lining fluid (ELF) following intravenous and pulmonary dosing have not been evaluated in a large-animal model with pulmonary architecture similar to that of humans. Six merino sheep (34 to 43 kg body weight) received an intravenous or pulmonary dose of 4 to 8 mg/kg CMS (sodium) or 2 to 3 mg/kg colistin (sulfate) in a 4-way crossover study. Pulmonary dosing was achieved via jet nebulization through an endotracheal tube cuff. CMS and colistin were quantified in plasma and bronchoalveolar lavage fluid (BALF) samples by high-performance liquid chromatography (HPLC). ELF concentrations were calculated via the urea method. CMS and colistin were comodeled in S-ADAPT. Following intravenous CMS or colistin administration, no concentrations were quantifiable in BALF samples. Elimination clearance was 1.97 liters/h (4% interindividual variability) for CMS (other than conversion to colistin) and 1.08 liters/h (25%) for colistin. On average, 18% of a CMS dose was converted to colistin. Following pulmonary delivery, colistin was not quantifiable in plasma and CMS was detected in only one sheep. Average ELF concentrations (standard deviations [SD]) of formed colistin were 400 (243), 384 (187), and 184 (190) mg/liter at 1, 4, and 24 h after pulmonary CMS administration. The population pharmacokinetic model described well CMS and colistin in plasma and ELF following intravenous and pulmonary administration. Pulmonary dosing provided high ELF and low plasma colistin concentrations, representing a substantial targeting advantage over intravenous administration. Predictions from the pharmacokinetic model indicate that sheep are an advantageous model for translational research.
Insights
Pulmonary administration of colistin methanesulfonate (CMS) in sheep achieved high concentrations in lung fluid but low levels in plasma, unlike intravenous dosing. This suggests sheep are a valuable model for studying targeted lung drug delivery.
Area of Science:
- Pharmacology and Pharmaceutical Sciences
- Infectious Diseases
- Translational Medicine
Background:
- Colistin is crucial for treating multidrug-resistant Gram-negative bacterial infections, particularly in the lungs.
- Understanding the pharmacokinetics of colistin and its prodrug, colistin methanesulfonate (CMS), is vital for optimizing treatment.
- Previous pharmacokinetic data in large animal models with human-like pulmonary architecture are lacking.
Purpose of the Study:
- To evaluate the pharmacokinetics of CMS and colistin in plasma and epithelial lining fluid (ELF) following intravenous and pulmonary administration in a sheep model.
- To compare the drug distribution and targeting efficiency between intravenous and pulmonary dosing routes.
- To assess the suitability of the sheep model for translational research in pulmonary infections.
Main Methods:
- A 4-way crossover study in six merino sheep (34–43 kg) involving intravenous or pulmonary administration of CMS or colistin.
- Pulmonary delivery via jet nebulization through an endotracheal tube.
- Quantification of CMS and colistin in plasma and bronchoalveolar lavage fluid (BALF) using high-performance liquid chromatography (HPLC); ELF concentrations estimated via the urea method.
- Pharmacokinetic modeling using S-ADAPT.
Main Results:
- Intravenous CMS or colistin did not yield quantifiable concentrations in BALF.
- Pulmonary CMS administration resulted in high average ELF colistin concentrations (e.g., 400 mg/L at 1 hour) with minimal plasma detection.
- Approximately 18% of the CMS dose was converted to active colistin.
- Pharmacokinetic modeling accurately described CMS and colistin disposition in plasma and ELF for both administration routes.
Conclusions:
- Pulmonary administration of CMS offers a significant targeting advantage, achieving high concentrations in the lung's epithelial lining fluid while minimizing systemic exposure.
- The sheep model demonstrates a suitable pulmonary architecture and pharmacokinetic profile for studying colistin's efficacy in treating lung infections.
- These findings support the use of sheep as a valuable preclinical model for translational research on inhaled antibiotics.
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