Population Pharmacokinetics of Colistin Methanesulfonate in Rats: Achieving Sustained Lung Concentrations of Colistin for Targeting Respiratory Infections

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142

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.

Section: Discussionmentioning

confidence: 55%

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

Yapa

Patel

et al. 2014

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142

“…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.…”

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confidence: 99%

“…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).…”

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confidence: 99%

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

Lin

Zhou

Cheah

et al. 2017

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Colistin is often administered by inhalation and/or the parenteral route for the treatment of respiratory infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa. However, limited pharmacokinetic (PK) and pharmacodynamic (PD) data are available to guide the optimization of dosage regimens of inhaled colistin. In the present study, PK of colistin in epithelial lining fluid (ELF) and plasma was determined following intratracheal delivery of a single dose of colistin solution in neutropenic lung-infected mice. The antimicrobial efficacy of intratracheal delivery of colistin against three P. aeruginosa strains (ATCC 27853, PAO1, and FADDI-PA022; MIC of 1 mg/liter for all strains) was examined in a neutropenic mouse lung infection model. Dose fractionation studies were conducted over 2.64 to 23.8 mg/kg of body weight/day. The inhibitory sigmoid model was employed to determine the PK/PD index that best described the antimicrobial efficacy of pulmonary delivery of colistin. In both ELF and plasma, the ratio of the area under the unbound concentration-time profile to MIC (fAUC/MIC) was the PK/PD index that best described the antimicrobial effect in mouse lung infection (R 2 ϭ 0.60 to 0.84 for ELF and 0.64 to 0.83 for plasma). The fAUC/MIC targets required to achieve stasis against the three strains were 684 to 1,050 in ELF and 2.15 to 3.29 in plasma. The histopathological data showed that pulmonary delivery of colistin reduced infection-caused pulmonary inflammation and preserved the integrity of the lung epithelium, although colistin introduced mild pulmonary inflammation in healthy mice. This study showed pulmonary delivery of colistin provides antimicrobial effects against MDR P. aeruginosa lung infections superior to those of parenteral administrations. For the first time, our results provide important preclinical PK/PD information for optimization of inhaled colistin therapy.

“…One or two compartments were assessed to describe TOB PK in plasma, but the one-compartment model was kept. TOB PK in ELF were first tested with one ELF compartment with a fixed physiological volume (V ELF ϭ 30 l · kg Ϫ1 ) as previously described (2, 3) and with the addition of a depot compartment (2), but two compartments with distinct volumes (V ELF1 , V ELF2 ) were necessary to reflect the previously described complexity of ELF PK (8). In the final model, compartments were connected by two-direction equilibrium distribution clearances, but the addition of an influx clearance from the ELF1 compartment to the central compartment was necessary for satisfactory data fitting.…”

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confidence: 99%

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

Marchand

Grégoire

Brillault

et al. 2015

The aim of this study was to determine the biopharmaceutical characteristics of tobramycin (TOB) after nebulization in rats. TOB was administered by intravenous (i.v.) bolus or intratracheal nebulization (3 mg · kg ؊1 ), and concentrations were determined in plasma and epithelial lining fluid (ELF) by liquid chromatography-tandem mass spectrometry. The ratio of the TOB concentration in ELF to the plasma area under the curve (AUC) was more than 200 times as high after NEB as after i.v. bolus administration, indicating that TOB nebulization offers a biopharmaceutical advantage over i.v. administration. Much higher intrapulmonary antibiotic concentrations may be achieved after nebulization (NEB) than after systemic administration, which may be of value for the treatment of pulmonary infections (1). However, this potential advantage may vary between compounds and could be much greater for antibiotics with a weak rather than a strong ability to permeate membranes, as recently shown for colistin (2) in comparison with ciprofloxacin or moxifloxacin (3). The aim of this study was to confirm this hypothesis by investigating the pulmonary pharmacokinetics (PK) of tobramycin (TOB), another antibiotic with a weak ability to permeate membranes that is clinically available for pulmonary administration, by using the same standardized protocol as before (2).Transepithelial transport across Calu-3 monolayers was tested to determine the apparent ability of TOB to permeate membranes (P app ) (4, 5). Animal experiments were approved by the Poitou Charentes Ethic Committee (COMETHEA) and registered by the French Ministry of Higher Education and Research (01733.01). Male Sprague-Dawley rats (n ϭ 50, 300 to 350 g; Janvier Laboratories, Le Genest-St-Isle, France) were used and housed as previously described (2). A first group of anesthetized rats received a 3-mg · kg Ϫ1 bolus dose of TOB (TOB sulfate solution, 50 mg · ml Ϫ1 , Nebcine; Erempharma) by the tail vein. A second group of anesthetized rats received the same dose of TOB (100 l) by intratracheal NEB under anesthesia (2, 3). In the two groups, bronchoalveolar lavage (BAL) fluid and blood samples were collected 0.25, 0.5, 1, 2.5, and 4 h after TOB administration (four or five rats per sampling time) (2, 3). The TOB assay used was adapted from a previously described method (6). A Waters Alliance 2695 separation module coupled with a Waters Micromass Quattro micro API tandem mass spectrometer was used. Chromatographic separation was done with an X bridge C 18 column (5.0 m, 150 by 2.1 mm [inside diameter]; Waters, St-Quentin en Yvelines, France) with a mobile phase composed of 0.1% (vol/vol) formic acid in water and 0.1% formic acid in acetonitrile (75:25, vol/vol) at a flow rate of 0.2 ml · min Ϫ1 . Quantification was performed in the positive-ion mode with multiple-reaction monitoring of m/z transitions 468.2 ¡ 163.1 for TOB and 448.2 ¡ 160.2 for sisomycin, the internal standard. The intraday and interday variabilities in plasma and BAL fluid were determined at three concentratio...