title: Population pharmacokinetics of colistin methanesulfonate in rats: achieving sustained lung concentrations of colistin for targeting respiratory infections.
abstract: Colistin methanesulfonate (CMS), the inactive prodrug of colistin, is administered by inhalation for the management of respiratory infections. However, limited pharmacokinetic data are available for CMS and colistin following pulmonary delivery. This study investigates the pharmacokinetics of CMS and colistin following intravenous (i.v.) and intratracheal (i.t.) administration in rats and determines the targeting advantage after direct delivery into the lungs. In addition to plasma, bronchoalveolar lavage (BAL) fluid was collected to quantify drug concentrations in lung epithelial lining fluid (ELF). The resulting data were analyzed using a population modeling approach in S-ADAPT. A three-compartment model described the disposition of both compounds in plasma following i.v. administration. The estimated mean clearance from the central compartment was 0.122 liters/h for CMS and 0.0657 liters/h for colistin. Conversion of CMS to colistin from all three compartments was required to fit the plasma data. The fraction of the i.v. dose converted to colistin in the systemic circulation was 0.0255. Two BAL fluid compartments were required to reflect drug kinetics in the ELF after i.t. dosing. A slow conversion of CMS (mean conversion time [MCTCMS] = 3.48 h) in the lungs contributed to high and sustained concentrations of colistin in ELF. The fraction of the CMS dose converted to colistin in ELF (fm,ELF = 0.226) was higher than the corresponding fractional conversion in plasma after i.v. administration. In conclusion, pulmonary administration of CMS achieves high and sustained exposures of colistin in lungs for targeting respiratory infections.
authors.affiliation: Drug Delivery, Disposition, and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
authors.forename: Shalini
authors.initials: SWS
authors.lastname: Yapa
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Christopher J H
authors.initials: CJ
authors.lastname: Porter
authors.forename: Roger L
authors.initials: RL
authors.lastname: Nation
authors.forename: Kashyap
authors.initials: K
authors.lastname: Patel
authors.forename: Michelle P
authors.initials: MP
authors.lastname: McIntosh
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003091:Colistin / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008168:Lung / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D003091:Colistin
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