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

Abstract

dThe purpose of this study was to define the pulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and formed colistin following intravenous (i.v.) and inhaled administration in cystic fibrosis (CF) patients. Six CF subjects were administered nebulized CMS doses of 2 and 4 million IU and an i.v. CMS infusion of 150 mg of colistin base activity. Blood plasma, sputum, and urine samples were collected for 12 to 24 h postdose. To assess the tolerability of the drug, lung function tests, blood serum creatinine concentrations, and adverse effect reports were recorded. All doses were well tolerated in the subjects. The pharmacokinetic parameters for CMS following i.v. delivery were consistent with previously reported values. Sputum concentrations of formed colistin were maintained at <1.0 mg/liter for 12 h postdose. Nebulization of CMS resulted in relatively high sputum concentrations of CMS and formed colistin compared to those resulting from i.v. administration. The systemic availability of CMS was low following nebulization of 2 and 4 million IU (7.93% ؎ 4.26% and 5.37% ؎ 1.36%, respectively), and the plasma colistin concentrations were below the limit of quantification. Less than 2 to 3% of the nebulized CMS dose was recovered in the urine samples in 24 h. The therapeutic availability and drug targeting index for CMS and colistin following inhalation compared to i.v. delivery were significantly greater than 1. Inhalation of CMS is an effective means of targeting CMS and formed colistin for delivery to the lungs, as high lung exposure and minimal systemic exposure were achieved in CF subjects.

Pharmacokinetics/Pharmacodynamics of Pulmonary Delivery of Colistin against Pseudomonas aeruginosa in a Mouse Lung Infection Model

“…Colistin was rapidly absorbed into the systemic circulation with an average bioavailability of approximately 100%, which was significantly higher than the 31 to 69% observed in rats (8,23). Interestingly, the bioavailability following intratracheal administration of CMS in rats was also 100% (6), which was significantly higher than that observed in humans (7.93% Ϯ 4.26% and 5.37% Ϯ 1.36%, respectively, for 1 and 2 million IU CMS) (9). This low systemic absorption observed in humans highlights the targeting advantage of intratracheal delivery of CMS considering nephrotoxicity and neurotoxicity (9).…”

“…Interestingly, the bioavailability following intratracheal administration of CMS in rats was also 100% (6), which was significantly higher than that observed in humans (7.93% Ϯ 4.26% and 5.37% Ϯ 1.36%, respectively, for 1 and 2 million IU CMS) (9). This low systemic absorption observed in humans highlights the targeting advantage of intratracheal delivery of CMS considering nephrotoxicity and neurotoxicity (9). The significantly higher bioavailability of colistin observed in mice was most likely attributed to the mechanism that was involved in the uptake of the antibiotic by the bronchial epithelium.…”

“…Inhalation therapy of colistin reduces systemic exposure and thus minimizes potential systemic side effects such as nephrotoxicity (1,12). PK studies in rats (6)(7)(8) and cystic fibrosis patients (9) have clearly demonstrated that nebulization of CMS/colistin resulted in much higher drug exposure in the epithelial lining fluid (ELF) or sputum than by systemic administration. The superior efficacy of nebulized CMS/colistin against lung infections caused by P. aeruginosa and Acinetobacter baumannii has been demonstrated in porcine (13) and mouse (14) lung infection models.…”

“…Recent pharmacokinetics/pharmacodynamics (PK/PD) and clinical studies demonstrate that intrave-nous CMS is suboptimal in treating respiratory tract infections caused by P. aeruginosa because of the very low exposure in the lungs and dosing-limiting nephrotoxicity (6)(7)(8)(9). In a PK/PD study against P. aeruginosa after parenteral administration in the mouse thigh and lung infection models, the ratio of the area under the unbound concentration-time profile to MIC (fAUC/MIC) required to achieve stasis for treating respiratory infection was approximately 4-fold higher than that required for treating thigh infection (4).…”

Efficacy of nebulized colistin-based therapy without concurrent intravenous colistin for ventilator-associated pneumonia caused by carbapenem-resistant Acinetobacter baumannii

“…Recent meta-analyses showed the benefits of nebulized colistin for VAP caused by multidrug-resistant pathogens; however, the role of this form of colistin might be adjunctive to intravenous colistin (27)(28)(29). We posit that the use of nebulized colistin can be supported by pharmacokineticpharmacodynamic (PK-PD) data regarding antimicrobial efficacy and delivery to the lungs (10,11,30), and that our present study has important implications which suggests that nebulized colistin may be used for VAP caused by CRAB, even without concurrent intravenous administration. However, nebulized colistin should be considered to be used with other systemic antibiotics active against CRAB isolates until further well-designed clinical trials based on randomization confirm the efficacy of nebulized colistin monotherapy in the treatment of VAP due to CRAB.…”