pulmonary pharmacokinetics of colistin following ... · pulmonary pharmacokinetics of colistin...

Pulmonary Pharmacokinetics of Colistinfollowing Administration of Dry PowderAerosols in Rats

Yu-Wei Lin,a Qi Tony Zhou,b Yang Hu,c Nikolas J. Onufrak,d Siping Sun,a

Jiping Wang,c Alan Forrest,d Hak-Kim Chan,a Jian Lie

Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales,Australiaa; Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, WestLafayette, Indiana, USAb; Drug Delivery, Disposition, and Dynamics, Monash Institute of PharmaceuticalSciences, Monash University, Parkville, Victoria, Australiac; Department of Pharmacotherapy and ExperimentalTherapeutics, Eshelman School of Pharmacy, The University of North Carolina, Chapel Hill, North Carolina,USAd; Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton,Victoria, Australiae

ABSTRACT Colistin has been administered via nebulization for the treatment of re-spiratory tract infections. Recently, dry powder inhalation (DPI) has attracted increas-ing attention. The current study aimed to investigate the pharmacokinetics (PK) ofcolistin in epithelial lining fluid (ELF) and plasma following DPI and intravenous (i.v.)administration in healthy Sprague-Dawley rats. Rats were given colistin as DPI intra-tracheally (0.66 and 1.32 mg base/kg of body weight) or i.v. injection (0.66 mg base/kg). Histopathological examination of lung tissue was performed at 24 h. Colistinconcentrations in both ELF and plasma were quantified, and a population PK model wasdeveloped and compared to a previously published PK model of nebulized colistin inrats. A two-compartment structural model was developed to describe the PK of colistinin both ELF and plasma following pulmonary or i.v. administration. The model-estimatedclearance from the central plasma compartment was 0.271 liter/h/kg (standard error[SE] � 2.51%). The transfer of colistin from the ELF compartment to the plasma com-partment was best described by a first-order rate constant (clearance of colistin from theELF compartment to the plasma compartment � 4.03 � 10�4 liter/h/kg, SE � 15%).DPI appeared to have a higher rate of absorption (time to the maximum concentra-tion in plasma after administration of colistin by DPI, �10 min) than nebulization(time to the maximum concentration in plasma after administration of colistin bynebulization, 20 to 30 min), but the systemic bioavailabilities by the two routes ofadministration were similar (�46.5%, SE � 8.43%). Histopathological examination re-vealed no significant differences in inflammation in lung tissues between the twotreatments. Our findings suggest that colistin DPI is a promising alternative tonebulization considering the similar PK and safety profiles of the two forms ofadministration. The PK and histopathological information obtained is critical forthe development of optimal aerosolized colistin regimens with activity againstlung infections caused by Gram-negative bacteria.

KEYWORDS polymyxin, colistin, dry powder, pulmonary delivery, disposition

Respiratory tract infections caused by multidrug-resistant (MDR) Gram-negativebacteria are a major public health burden globally (1, 2). With their increasing

prevalence and a scarcity of effective antibiotics, respiratory tract infections caused bythese superbugs are alarmingly dangerous, often resulting in high rates of morbidityand mortality (3). Colistin (i.e., polymyxin E), a polypeptide antibiotic, has been increas-ingly used as a last resort for the treatment of respiratory tract infections caused byMDR Gram-negative pathogens (4, 5). Traditional parenteral administration of colistin

Received 25 May 2017 Returned formodification 10 July 2017 Accepted 6August 2017

Accepted manuscript posted online 14August 2017

Citation Lin Y-W, Zhou QT, Hu Y, Onufrak NJ,Sun S, Wang J, Forrest A, Chan H-K, Li J. 2017.Pulmonary pharmacokinetics of colistinfollowing administration of dry powderaerosols in rats. Antimicrob Agents Chemother61:e00973-17. https://doi.org/10.1128/AAC.00973-17.

Copyright © 2017 American Society forMicrobiology. All Rights Reserved.

Address correspondence to Hak-Kim Chan,[email protected], or Jian Li,[email protected].

Y.-W.L. and Q.T.Z. contributed equally to thisarticle.

PHARMACOLOGY

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may not provide optimal efficacy for the treatment of respiratory tract infections, asrecent animal studies demonstrated the very limited exposure of colistin in theepithelial lining fluid (ELF) (6–10). A recent pharmacokinetic/pharmacodynamic (PK/PD)study of parenteral colistin against Pseudomonas aeruginosa in mouse thigh and lunginfection models was conducted; the ratio of the area under the unbound (free) plasmaconcentration-time curve over the MIC (fAUCplasma/MIC) required to achieve bacterios-tasis in the lungs was approximately 2.5- to 5-fold higher than that required to achievebacteriostasis in the thighs (11). Increasing the dose of parenteral colistin is not feasibledue to the dose-limiting nephrotoxicity of colistin (12, 13), which highlights the needfor alternative routes of colistin administration to treat respiratory tract infections.

Pulmonary administration of colistin can achieve a high drug exposure in the lungswhile minimizing systemic exposure and nephrotoxicity. The advantage of the pulmo-nary delivery of colistin has been illustrated in several preclinical (6–10, 14) and clinical(15, 16) PK studies. Yapa et al. reported in a clinical study that pulmonary nebulizationof colistin methanesulfonate (CMS) (2 million and 4 million international units oncedaily, equivalent to 60 and 120 mg colistin base activity [CBA], respectively) resulted inhigher exposure of CMS and formed colistin in sputum (maximum sputum concentra-tion [Cmax, sputum] � 2 to 21 mg/liter) than that achieved after intravenous (i.v.)administration (Cmax, sputum � 0.12 to 0.72 mg/liter) (15). In a PK/PD study of colistinagainst P. aeruginosa ATCC 27853 in the mouse lungs, the required plasma fAUCplasma/MIC following pulmonary administration (2.99) was 11-fold lower than that followingsubcutaneous administration (34.1) (11, 17). Nebulized antimicrobials have improvedthe life expectancy of patients with cystic fibrosis (CF) (18–20); however, they requireexpensive and complicated delivery devices and prolonged administration times (21–27), and the delivery efficiency is low (�15% of the administered dose reaches thelungs following jet nebulization) (28). Consequently, patient compliance with nebulizedantibiotics is low (29, 30). Dry powder inhalation (DPI) provides a suitable alternative, aspowder inhaler devices are portable, easy to use, and, most importantly, able to deliverdrug efficiently (31–33) and improve efficacy and patient compliance (34, 35).

To date, the majority of in vivo studies of aerosolized CMS and colistin have focusedon nebulization (6–10, 14, 15, 36–39), whereas only a few investigated DPI (23–26). Thesafety and efficacy of jet-milled CMS/colistin powder have been evaluated in healthyvolunteers and patients with CF (23–26). However, these DPI formulations have arelatively low aerosolization efficiency (40% in the fine-particle fraction [FPF]) (23). Inour earlier study, inhalable dry powder formulations of colistin with a high aerosoliza-tion efficiency were developed by spray-drying (total FPF, �83% via an Aerolizerdevice) (22). These highly dispersible colistin DPI formulations provide higher levels ofdrug deposition in the lungs and thus have a greater potential for the effectivetreatment of respiratory infections caused by MDR Gram-negative bacteria (40, 41).Although a CMS DPI product (Colobreathe) has been approved in Europe, the dosageregimens of DPI have not been appropriately optimized on the basis of PK/PD studies(32). The present study aimed to investigate the PK of our highly efficient colistin DPIformulation in healthy rats after pulmonary administration.

RESULTS

Following DPI, colistin was rapidly absorbed into the systemic circulation, with themaximum plasma concentration (Cmax, plasma) being detected within 10 min afteradministration, followed by a biexponential decline over the 12-h sampling period (Fig.1 and Table 1). High levels of colistin exposure in the ELF were achieved following DPI(maximum ELF concentration [Cmax, ELF] � 400.1 � 44.9 and 607.0 � 58.9 mg/liter fordoses of 0.66 and 1.32 mg colistin base/kg of body weight, respectively; Table 1) andwas maintained for at least 12 h (Fig. 1). The concentrations of urea measured in thebronchoalveolar lavage fluid (BALF) and plasma were 1.01 � 0.43 mg/dl and 48 � 10mg/dl, respectively.

The disposition of colistin in the ELF and plasma following DPI and i.v. administra-tion was best described by two compartments (Fig. 2 to 4 ; see also Fig. S1 in the

Lin et al. Antimicrobial Agents and Chemotherapy

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supplemental material). The PK parameters generated from the population PK modelare listed in Table 2. The estimated apparent volumes of distribution in the ELF (VELF)in ELF compartments 1 and 2 (VE1 and VE2, respectively; manifested as ELF1 and ELF2in Fig. 4, respectively) were 2.90 � 10�5 liter/kg (standard error [SE] � 35.7%) and9.67 � 10�4 liter/kg (SE � 18.8%), respectively. The estimated total systemic bodyclearance (CLtotal) from the central plasma compartment for colistin was 0.271 liter/h/kg(SE � 2.51%). A first-order process was sufficient to describe the transfer of colistin fromELF to the central plasma compartment. The estimated systemic bioavailability of DPI(FDPI) was 46.5% (SE � 8.43%) (Table 2).

Histopathological examination of the lung tissue at 24 h following DPI and wet

FIG 1 (A) Colistin ELF concentration-time profiles following DPI of 0.66 mg base/kg and 1.32 mg base/kgcolistin. The colistin ELF concentration following i.v. bolus administration was below the LOQ. (B) Totalplasma colistin concentration-time profiles following DPI and i.v. administration of colistin in healthySprague-Dawley rats. Each symbol represents the mean � standard deviation (SD; n � 3 or more). *, theconcentration is below the LOQ (0.10 mg/liter).

TABLE 1 PK parameters for colistin in healthy rats following DPI administrationa

DoseCmax, ELF

(mg/liter)Cmax, plasma

(mg/liter) Tmax (min)

Single pulmonary dose of:0.66 mg base/kg 400.1 � 44.9 0.65 � 0.32 101.32 mg base/kg 607.0 � 58.9 1.66 � 0.69 10

Single i.v. dose of 0.66 mg base/kg �LOQ NA NAaData are presented as means � standard deviations. NA, not applicable.

PK of Aerosolized Colistin Dry Powder Antimicrobial Agents and Chemotherapy



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FIG 2 Visual predictive checks for colistin in plasma following DPI of 0.66 mg base/kg (A) and 1.32 mgbase/kg (B) and i.v. administration of 0.66 mg base/kg (C). Solid line, the median model-predictedconcentrations (P50); broken lines, model-predicted 10th percentile (P10) and 90th percentile (P90)concentrations; solid dots, observed concentrations. After 4 h, the 10th percentile concentration ap-proaches zero. *, the concentration is below the LOQ (0.10 mg/liter).




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nebulization of colistin showed mean pathological scores of about 1.0 to �2.0 (indi-cating mild damage), whereas the saline-treated group had a mean pathological scoreof 0.3 (indicating no damage; Table 3). Furthermore, no significant difference in thepathological scores was observed among the lung tissue samples obtained at 24 h fromthe nebulization (1.32 mg base/kg) and DPI (0.66 mg base/kg) groups (Table 3). Evenwith the highest dose (1.32 mg base/kg), DPI and wet nebulization resulted in milddamage in the lung tissue with similar pathological scores (1.9 and 1.5, respectively)(Table 3).

DISCUSSION

Aerosolized polymyxin therapy administered via nebulization has become a com-mon complementary practice for the treatment of respiratory tract infections, such asthose in CF patients (42, 43) and in critically ill patients with ventilator-associatedpneumonia (44, 45). With recent advancements in particle engineering technology, wehave successfully formulated a colistin dry powder with a markedly higher aerosoliza-tion efficiency (total FPF, �83% via an Aerolizer device) than those colistin dry powderformulations in the previous studies (22, 25, 26). DPI offers a potentially superioralternative inhalational delivery method that provides a better drug deposition in thelungs than nebulization and that results in a higher rate of patient compliance than

FIG 3 Visual predictive checks for colistin in ELF following DPI of 0.66 mg base/kg (A) and 1.32 mgbase/kg colistin (B). Solid line, the median model-predicted concentrations (P50); broken lines, themodel-predicted 10th percentile (P10), and 90th percentile (P90) concentrations; solid dots, observedconcentrations.




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nebulization (23–26, 33). This is the first preclinical study to investigate the PK of thespray-dried colistin powder aerosol in healthy rats.

In the present study, a population PK model was constructed to better understandthe disposition of colistin in ELF and plasma following pulmonary and i.v. administra-tion. Data were distributed around the line of identity (see Fig. S1 in the supplementalmaterial), and the majority of the observed concentrations were scattered within the10th and 90th percentiles (Fig. 2 and 3). Therefore, our population PK model welldescribed colistin exposure in ELF (overall R2 � 0.87) and plasma (overall R2 � 0.91).The model revealed that the plasma concentrations of colistin rapidly decreasedfollowing i.v. and pulmonary administration (Fig. 1). Following administration of colis-tin, the model-predicted total systemic body clearance (CLtotal � 0.271 liter/h/kg, SE �

2.51%; Table 2) and volume of distribution of the central plasma compartment (Vc �

TABLE 2 Estimated values of population PK parameters for colistin in healthy rats following DPI or i.v. administration

Parameter Description Unit Estimated value SE (%)

VE1 Vol of distribution in ELF1 (ELF compartment) liter/kg 2.90 � 10�5 35.7VE2 Vol of distribution in ELF2 (peripheral lung compartment) liter/kg 9.67 � 10�4 18.8Vc Volume of distribution in central plasma compartment liter/kg 0.572 17.9Vp Volume of distribution in peripheral plasma compartment liter/kg 1.47 35.3CLD, ELF ELF intercompartmental clearance liter/h/kg 4.26 � 10�4 37.8CLD, plasma Plasma intercompartmental clearance liter/h/kg 0.172 24.3CLtotal Total systemic body clearance liter/h/kg 0.271 2.51CLELF, plasma Intercompartmental clearance from ELF to plasma liter/h/kg 4.03 � 10�4 15.0CLplasma, ELF Intercompartmental clearance from plasma to ELF liter/h/kg 9.93 � 10�7 46.0fu Unbound fraction 0.44 (fixed) NAa

FDPI Bioavailability % 46.5 8.43aNA, not applicable.

FIG 4 A population PK structural model describing the disposition of colistin in ELF and plasma followingDPI or i.v. administration of colistin. The parameters are presented in Table 2.




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0.572 liter/kg, SE � 17.9%; Table 2) were comparable to those reported in the literature(Vc � 0.22 to 0.43 liter/kg and CLtotal � 0.22 to 0.43 liter/h/kg) (7, 10, 36, 46).

In the current study, the PK linearity observed with colistin following DPI adminis-tration in healthy Sprague-Dawley rats is consistent with the findings of Yapa et al.following wet nebulization in rats (7). In contrast, PK nonlinearity was reported byGontijo et al. following wet nebulization of colistin in rats (10). A more complex PKmodel with Michaelis-Menten (nonlinear) kinetics was proposed by Gontijo et al. todescribe the transfer of colistin across the lung alveolar epithelium after nebulization(10). However, we did not find a significant improvement in model fit upon incorpo-ration of such a process, with a first-order rate constant being sufficient to describe ourdata. This is in agreement with the PK models developed for rats (6), sheep (14), baboonmonkeys (9), and critically ill patients (16) after the nebulization of colistin. Themechanism of colistin transport across the lung epithelium remains unclear and isbeing investigated in our laboratory.

The systemic absorption of colistin was faster in rats when it was administered asDPI, with the time to reach the maximum plasma concentration (Tmax) being 20 to 30min for the nebulization and �10 min for DPI (7). The slightly faster absorption ratefollowing DPI is very likely due to the higher aerosolization efficiency of spray-driedcolistin powder and the differential distribution of PEPT2 in different regions of therespiratory tract (47, 48). As opposed to wet nebulization using a MicroSprayer device,the large fine-particle fraction of the colistin dry powder upon pulmonary administra-tion is able to reach deeper airways, where PEPT2 is abundantly expressed (47–49).Such a faster absorption rate with DPI than with nebulization was also observed in ourearlier study, where the Kv1.3-blocking peptide HsTX1[R14A] was administered tohealthy rats using the same Penn-Century device used in the present study (50).Despite the more rapid absorption of the powder formulation, the systemic bioavail-ability of colistin solution (Fsolution � 31 to 69%) (7, 10) and the spray-dried powderformulation (FDPI � 46.5%) (Table 2) was similar in healthy Sprague-Dawley rats. Thetranslation of PK data from rats to humans after pulmonary administration has re-mained challenging, as the airway anatomy of rats differs from that of humans (51) andthe Penn-Century device dispersed powder differently from the clinical dry powderinhaler (52). With the Penn-Century device, the colistin dry powder is dispersedpassively into the lungs, which may not be comparable to the dispersal achieved withclinically used dry powder inhalers (i.e., Twincer), with which patients are required toactively inhale CMS/colistin dry powder (25–27). Importantly, the human PK of CMSadministered via clinical dry powder inhalers are likely influenced by interindividual andinterdevice variabilities (27). Clinical studies are thus needed to characterize the extentof potential patient- and device-specific differences in the PK of DPI of polymyxins.

Consistent with the observation following the nebulization of colistin, DPI treatmentresulted in the prolonged and extensive exposure of colistin in the ELF (Fig. 1) (6, 7, 10,36). The colistin exposure in the ELF achieved after DPI (0.35 mg base/kg colistin),reflected by an area under the concentration-time curve (AUC) from 0 to 4 postdosingfor ELF (AUC0 – 4 h,ELF; �328 mg · h/liter, calculated using PK simulation), was compa-

TABLE 3 Histopathological examination of the lungs of healthy rats following DPI ofcolistin

Dose(mg base/kg) Formulation

Time(h)

No. ofrats

Mean pathologicalscore

Saline Solution 0.5 1.0Saline Solution 24 0.30.66 Dry powder 0.5 4 1.50.66 Dry powder 24 4 1.01.32 Dry powder 0.5 4 1.81.32 Dry powder 2 4 1.21.32 Dry powder 6 4 0.81.32 Dry powder 24 4 1.91.32 Solution 24 4 1.5




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rable to that following wet nebulization of 0.35 mg base/kg colistin in healthy rats(AUC0 – 4 h,ELF � �369 mg · h/liter) (10). It is important to appreciate that ELF exposurecan be influenced by VELF, which was variable in rat studies (7.6 � 5.8 to 110 � 23 �l)due to the different techniques used for the sampling of BALF and the urea quantifi-cation method utilized (6, 7, 10, 36).

A key finding of our current study is that colistin concentrations in ELF were muchhigher following DPI treatment (Cmax, ELF � 400.1 � 44.9 and 607.0 � 58.9 mg/liter forcolistin at 0.66 and 1.32 mg base/kg, respectively) than following i.v. administration,with the concentrations dramatically exceeding the MIC90 (�1 mg/liter) against P.aeruginosa for at least 12 h (Fig. 2) (53). Colistin ELF concentrations following i.v.administration were below the limit of quantitation (LOQ) of ELF (4.84 mg/liter, afterconsidering the dilution factor for the interconversion of BALF and ELF concentrations).The population PK model developed in our study facilitated the prediction of colistinconcentrations in ELF following i.v. administration. Our results show that the simulatedcolistin concentration in ELF after i.v. administration was well below the ELF LOQ(�4.84 mg/liter) at any time point. This was consistent with the observation in patientswith CF, in which a low concentration of formed colistin (�1 mg/liter) was observedfollowing i.v. administration of CMS (150 mg CBA) (15). Another important finding inour population PK model is that the model-estimated VE2 was larger than the model-estimated VE1 (Table 2). This potentially infers the binding of colistin to pulmonarysubstances, such as mucin (54) and pulmonary surfactant (55), or a significant distri-bution of colistin into lung epithelial cells in rats. This finding is consistent with theliterature that colistin accumulates in the lung tissue (56) and binds to lung epitheliumvia an electrostatic interaction (57).

Collectively, the population PK model developed in the current study suggests thatthe spray-dried colistin DPI formulation has PK properties (e.g., ELF exposure andsystemic bioavailability) comparable to those of the wet nebulized formulation. Themajority of CF patients usually require long-term nebulized colistin therapy (as CMS)(58). Although nebulized colistin therapy has significantly improved patients’ lifeexpectancy, the complex nebulization system may have a negative impact on thequality of life and compliance in patients (27). On the basis of the findings of previousclinical studies (59, 60), the inhalation of colistin via dry powder inhalers is an attractiveand effective alternative for the treatment of respiratory infections owing to theimproved convenience, reduced duration of administration, and positive effects onquality of life, compliance, and, possibly, therapeutic outcomes in patients (61).

Aerosolized colistin in both solution and dry powder forms may cause pulmonaryadverse effects, such as a cough or throat irritation (32). The mechanisms underlyingsuch effects are unclear but may be related to mast cell degranulation (62, 63). Thesafety of pulmonary administration of colistin solution was previously examined, andno significant inflammation or damage to the lungs was observed after a single doseof CMS or colistin in rats (the doses were not provided) (6, 7). In the present study, thesafety of colistin DPI at 0.66 and 1.32 mg base/kg was evaluated by histopathologicalexamination and compared to the findings obtained following a similar dose of colistinsolution (Table 3). The pulmonary administration of neither colistin solution nor DPIresulted in severe inflammation or damage to the lung epithelium (scores, 1.0 to �2.0,showing mild to moderate lesions). Our results indicate that DPI of colistin is as safe asnebulization in healthy rats. PK/PD/toxicodynamic optimization of aerosolized poly-myxins is needed in patients to minimize any potential side effects (i.e., bronchospasmand cough).

To the best of our knowledge, the PK model described here is the first detailedpreclinical PK model describing the disposition of colistin in ELF and plasma followingDPI in rats. Our study has shown that spray-dried colistin DPI achieves drug exposurein ELF dramatically higher than that achieved by i.v. administration. Furthermore,histopathological examination of lung tissue demonstrates that DPI has safety compa-rable to that of wet nebulization. DPI is a promising alternative to nebulization,especially considering the convenience of the dry powder inhaler and its positive




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impacts on patient compliance. With the increasing incidence of life-threatening lunginfections caused by MDR Gram-negative bacteria, the PK and safety informationobtained here is critical to the optimization of DPI of polymyxin therapy in patients.

MATERIALS AND METHODSChemicals. Colistin sulfate (lot number 08M1526V; �15,000 U/mg) was purchased from Sigma-

Aldrich (St. Louis, MO, USA). All organic solvents were of analytical grade unless stated otherwise.Colistin dry powder. Colistin dry powder was prepared by spray-drying as previously described (22).

Briefly, colistin sulfate was dissolved in water and spray-drying was performed using a B-290 mini-spraydryer (Buchi Laboratories, Flawil, Switzerland). The spray-drying conditions were as follows: inlet tem-perature, 80°C; atomizer setting, 700 liter/h; aspirator, 40 m3/h; and feed rate, 2 ml/min. The spray-driedsamples were stored in a desiccator at room temperature.

Animals. All rat experiments (see Table S1 in the supplemental material) were approved by theAnimal Ethics Committee of the Monash Institute of Pharmaceutical Sciences, Monash University, andconducted in accordance with the Australian Code of Practice for the Care and Use of Animals forScientific Purposes. Male Sprague-Dawley rats (weight, 300 to 350 g; Monash Animal Research Platform,Victoria, Australia) were housed with a 12-h light/12-h dark cycle at ambient temperature (21 � 3°C) anda relative humidity of 40 to 70%. Food and water were available ad libitum.

Pharmacokinetic studies. Prior to the PK studies, the right carotid artery and right jugular vein ofrats were cannulated for blood collection and i.v. drug administration, respectively (6, 7). Followingsurgery, the rats were individually housed in metabolic cages and allowed to recover overnight.

Dosing of colistin. A single-dose PK study was performed in healthy rats following administration ofan i.v. bolus of colistin at 0.66 mg base/kg via the right jugular vein (n � 3). Blood samples were collectedat 10, 20, and 30 min and 1, 1.5, 2, 3, 4, 6, 12, and 24 h postadministration. Extra rats (n � 3 per time point)received an i.v. bolus of colistin at 0.66 mg base/kg for BALF collection (6, 7) at 10 min and 2, 6, and 12h postadministration.

DPI of colistin. Two groups of rats were utilized to characterize the pulmonary and systemic PK ofcolistin following DPI. In group 1, rats were given a colistin powder formulation (0.66 and 1.32 mgbase/kg) by pulmonary administration. Briefly, rats were anesthetized using gaseous isoflurane (AbbottAnimal Health, Abbott Park, IL). The anesthetized rats were placed on a Perspex support in a verticalupright position. The pulmonary administration was performed using a dry powder insufflator (DP-4M;Penn-Century, Glenside, PA) (52). The chamber of the dry powder insufflator was loaded with colistin drypowder, and 6 puffs of 2 ml air were applied via an air pump (AP-1; Penn-Century, Glenside, PA) todisperse the powder. The total drug administration time was approximately 20 to 30 s per animal. Thedry powder insufflator was weighed before and after administration to determine the amount of colistindelivered. On average, more than 90% of the colistin powder was dispersed and emitted from the device.The insufflator was cleaned with 10 puffs of 3 ml air before and after each experiment to remove excesspowder in the chamber and cannula. Blood samples were collected via the right carotid artery at 10 and30 min and 1, 2, and 4 h after pulmonary administration. In group 2, rats were given colistin dry powder(0.66 and 1.32 mg base/kg) by pulmonary administration, and BALF was collected at 10 and 30 min and1, 2, 4, 6, and 12 h (6, 7). In group 1, at least 3 animals were included per dosage regimen, while in group2, at least 3 animals were employed per time point.

The maximum dosage regimens for i.v. and pulmonary administration of the colistin dry powderaerosol were chosen on the basis of its tolerability in rats (6). The lowest dose selected was based uponthe LOQ of the method used for the analysis of colistin in plasma.

Measurement of colistin concentrations in plasma, BALF, and ELF. Colistin concentrations inplasma and BALF samples were determined by a validated liquid chromatography-mass spectrometry(LC-MS) method (64), with minor modifications. Briefly, BALF and plasma samples were deproteinizedwith 0.1% formic acid in acetonitrile (1:2 dilution) and centrifuged at 18,210 � g. For each analytical run,peak area ratios of the analyte (the sum of the peak areas for colistin A and colistin B) and the internalstandard (the sum of the peak areas for polymyxin B1 and polymyxin B2) were plotted against thenominal concentrations of the calibration standards. Linear least-squares regression analysis withoutweighting was performed to determine the linearity, intercept, and slope. Calibration curves wereprepared with blank BALF or plasma, and the concentrations ranged from 0.10 to 10.0 mg/liter. The LOQwas 0.10 mg/liter for both plasma and BALF samples. The inter- and intraday accuracy and precision ofthe assay for plasma and BALF samples are provided in Table S2. The VELF was determined using urea asan endogenous dilution marker (65). The urea concentrations in BALF and plasma were determined usinga QuantiChrom urea assay kit (Bioassay Systems, CA, USA). The standard curve was prepared with ureain Milli-Q water, and the linear detection range was from 0.08 mg/dl (13 �M) to 100 mg/dl (17 mM) urea.The accuracy and precision of the QuantiChrom urea assay kit for the measurement of the concentrationof urea in biological samples were examined previously (7). Quality control samples were prepared at 4levels, and the accuracy and precision of the kit at the 4 levels (1, 10, 25, and 50 mg/dl) were within 10%.

VELF was calculated as follows: VELF � ([urea]BALF/[urea]plasma) · VBALF, where [urea]BALF and [urea]plasma

are the urea concentrations (in milligrams per deciliter) in BALF and plasma, respectively, and VBALF is thevolume of BALF recovered.

The colistin concentration in ELF was calculated as follows: [colistin]ELF � [colistin]BALF · ([urea]plasma/[urea]BALF), where [colistin]ELF and [colistin]BALF are the colistin concentrations (in milligrams per liter) inELF and BALF, respectively.




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Population pharmacokinetic model. A nonlinear mixed-effects model was employed to character-ize the disposition of colistin in ELF and plasma following DPI in health rats. During PK analysis, severalstructural models were tested and evaluated using the Monte Carlo parametric expectation maximizationalgorithm (importance sampling, pmethod � 4) in the S-ADAPT program (version 1.57), facilitated by theS-ADAPT TRAN set of programs (66). In the final composite model, two compartments were required todescribe the kinetics of colistin in both ELF and plasma following pulmonary and i.v. administration. Theresidual error model was estimated using heteroscedastic error (additive and proportional) structures.The Beal M3 method was employed to handle concentrations below the LOQ (67). Graphical analysis ofgoodness-of-fit plots (e.g., observed concentration versus population predicted concentration) andobjective function values (reported as �1 � log likelihood in S-ADAPT) was employed to evaluate thesuitability of the model (68–70). A decrease in the objective function value of 1.92 units (chi-square testwith 1 degree of freedom) was considered significant. The final model was evaluated using the visualpredictive checks (71).

Histopathological examination of the lungs following treatment with aerosolized colistin.Histopathological examination of rat lung tissue was performed to compare the effect of colistin onpulmonary epithelial cells after the pulmonary administration of colistin by DPI and by nebulization.Treatment groups received either 0.66 or 1.32 mg base/kg colistin dry powder or 1.32 mg base/kg colistinsolution, and the control group received 50 �l saline. Rats were humanely killed at 0.5 and 24 h (0.66 mgbase/kg) or at 0.5, 2, 6, and 24 h (1.32 mg base/kg) following dosing. To avoid any artificial damage,bronchoalveolar lavage and cardiac puncture were not performed prior to tissue harvesting. To quantifythe extent of lung damage, a pathological grading system developed by the Australian PhenomicsNetwork was adapted (Australian Phenomics Network Histopathology and Organ Pathology Service,Victoria, Australia). Briefly, the severity and the nature of the histopathological changes in lung epithelialcells were graded as follows: score of 0, no changes or mild changes considered insignificant; score of1, mild damage; score of �2, mild to moderate damage; and score of �3, moderate to severe damage.Scoring and grading of the lungs were performed blind by histopathologists at the Australian PhenomicsNetwork Histopathology and Organ Pathology Service.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at https://doi.org/10.1128/AAC.00973-17.

SUPPLEMENTAL FILE 1, PDF file, 0.3 MB.

ACKNOWLEDGMENTSWe acknowledge the financial support from a National Health and Medical Research

Council (NHMRC) project grant (APP1065046). J.L. and A.F. are supported by a researchgrant from the National Institute of Allergy and Infectious Diseases of the NationalInstitutes of Health (R01 AI111965). Y.-W.L. is the recipient of an Australian postgrad-uate award. J.L. is an Australian NHMRC senior research fellow. This study utilized theAustralian Phenomics Network Histopathology and Organ Pathology Service at theUniversity of Melbourne.

The content is solely the responsibility of the authors and does not necessarilyrepresent the official views of the National Institute of Allergy and Infectious Diseasesor the National Institutes of Health.

We thank Tien Nguyen for her assistance.

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