Comparison between Colistin Sulfate Dry Powder and Solution for Pulmonary Delivery

Abstract

To assess the difference in the fate of the antibiotic colistin (COLI) after its pulmonary delivery as a powder or a solution, we developed a COLI powder and evaluated the COLI pharmacokinetic properties in rats after pulmonary administration of the powder or the solution. The amorphous COLI powder prepared by spray drying was characterized by a mass median aerodynamic diameter and fine particle fraction of 2.68 ± 0.07 µm and 59.5 ± 5.4%, respectively, when emitted from a Handihaler®. After intratracheal administration, the average pulmonary epithelial lining fluid (ELF): plasma area under the concentration versus time curves (AUC) ratios were 570 and 95 for the COLI solution and powder, respectively. However, the same COLI plasma concentration profiles were obtained with the two formulations. According to our pharmacokinetic model, this difference in ELF COLI concentration could be due to faster systemic absorption of COLI after the powder inhalation than for the solution. In addition, the COLI apparent permeability (Papp) across a Calu-3 epithelium model increased 10-fold when its concentration changed from 100 to 4000 mg/L. Based on this last result, we propose that the difference observed in vivo between the COLI solution and powder could be due to a high local ELF COLI concentration being obtained at the site where the dry particles impact the lung. This high local COLI concentration can lead to a local increase in COLI Papp, which is associated with a high concentration gradient and could produce a high local transfer of COLI across the epithelium and a consequent increase in the overall absorption rate of COLI.

Inhaled Colistimethate Sodium in the Management of Patients with Bronchiectasis Infected by Pseudomonas aeruginosa: A Narrative Review of Current Evidence

“… 31 In contrast, a much higher systemic bioavailability (46 to 64%) have been observed in rat models after intratracheal administration. 35 , 36 The reason for this difference is unclear, but it has been speculated that the diffusion of colistin across the bronchial epithelium is not only mediated by passive diffusion and that specific drug transporters might be implicated in the absorption of colistin – and the expression of these transporters might be different between species. 34 …”

“…Tewes et al found a lower exposure of the pulmonary epithelial lining fluid to colistin after intratracheal administration of SCM powder to rats, compared to SCM solution. 36 However, they attributed this difference to faster systemic absorption of the drug after the inhalation of powder and, as mentioned above, the PK of SCM absorption might be different in humans. Even using the same formulation, the PK could be different, depending on the delivery system (ie, the design of the nebulizer), although Ratjen et al found no significant differences in sputum colistin concentrations with two different nebulizers.…”

“…These studies agree, however, that high levels of colistin exposure are achieved in epithelial lining fluid (ELF) and sputum after inhalation, and that these levels are much higher than after intravenous administration. 29,31,[34][35][36][37][38] Systemic exposure after SCM inhalation is low. Concentrations of SCM and colistin can be on the order of 100 to 1000 times higher in the ELF than in plasma after administration of aerosolized SCM.…”

“…31 In contrast, a much higher systemic bioavailability (46 to 64%) have been observed in rat models after intratracheal administration. 35,36 The reason for this difference is unclear, but it has been speculated that the diffusion of colistin across the bronchial epithelium is not only mediated by passive diffusion and that specific drug transporters might be implicated in the absorption of colistin -and the expression of these transporters might be different between species. 34 The substantial pulmonary exposure and minimal systemic exposure observed after inhalation of SCM in humans imply that this route should be effective in maximizing the antibacterial effect in the respiratory system, while also minimizing toxicity.…”

Nebulized Colistin in Ventilator-Associated Pneumonia and Tracheobronchitis: Historical Background, Pharmacokinetics and Perspectives

“…Nebulization of high doses of CMS results in high lung tissue colistin concentrations with correspondingly low plasma colistin concentrations (< 2 µg/mL) (Figure 6c) suggesting limited diffusion into the systemic compartment [26,28,41,42,[75][76][77][78][79][80][81][82]. After the initial CMS nebulization of 2 million IU (Figure 8a,b), CMS and colistin plasma concentrations show quite similar pharmacokinetic profiles [79]: an early peak concentration for CMS (30 min), a delayed peak concentration for colistin (3 h) and a slow and progressive decrease in concentrations over the following hours.…”