Advances in experimental and mechanistic computational models to understand pulmonary exposure to inhaled drugs

European Journal of Pharmaceutical Sciences

Volumn 113, Issue , 2018, Pages 41-52

  Bäckman, Per ^a   Arora, Sumit ^e   Couet, William ^b   Forbes, Ben ^c   de Kruijf, Wilbur ^d   Paudel, Amrit ^e  

^a Global Respiratory Group   (United Kingdom)

^b UNIVERSITÉ DE POITIERS   (France)

^c KING'S COLLEGE LONDON   (United Kingdom)

^d Medspray BV   (Netherlands)

^e RESEARCH CENTER PHARMACEUTICAL ENGINEERING GMBH   (Austria)

Author keywords

Aerosol; Deposition; Dissolution; Drug delivery; PBPK; Permeation; Respiratory

Indexed keywords

RESPIRATORY TRACT AGENT;

ARTICLE; COMPUTER MODEL; DEVELOPMENT; DRUG DELIVERY SYSTEM; DRUG DISPOSITION; DRUG EXPOSURE; DRUG SOLUBILITY; DRUG TISSUE LEVEL; HUMAN; INHALATION; LUNG PARENCHYMA; PERMEABILITY; PREDICTION; PRIORITY JOURNAL; PRODUCT DEVELOPMENT; AEROSOL; BIOLOGICAL MODEL; CHEMISTRY; COMPUTER SIMULATION; DRUG RELEASE; INHALATIONAL DRUG ADMINISTRATION; LUNG; MEDICINAL CHEMISTRY; PHARMACOKINETICS; PROCEDURES; RESPIRATORY FUNCTION; SOLUBILITY; TISSUE DISTRIBUTION;

ADMINISTRATION, INHALATION; AEROSOLS; CHEMISTRY, PHARMACEUTICAL; COMPUTER SIMULATION; DRUG DELIVERY SYSTEMS; DRUG LIBERATION; HUMANS; LUNG; MODELS, BIOLOGICAL; PERMEABILITY; PHARMACOKINETICS; RESPIRATORY TRACT ABSORPTION; SOLUBILITY; TISSUE DISTRIBUTION;

EID: 85033724156     PISSN: 09280987     EISSN: 18790720     Source Type: Journal    
DOI: 10.1016/j.ejps.2017.10.030     Document Type: Article

References (99)

1. Anjivel, S., Asgharian, B., A multiple path model of particle deposition in the rat lung. Fundam. Appl. Toxicol. 28 (1995), 41–50.
2. Axelsson, B., Bäckman, P., Strandberg, P., Brattsand, R., Development of inhaled steroids based upon prodrugs with prolonged intraluminal retention. Schleimer, R.P., O'Byrne, P.M., Szefler, S.J., Brattsand, R., (eds.) Inhaled Steroids in Asthma: Optimizing Effects in the Airways, vol. 163, 2002, Marcel Dekker, Inc., New York, 565–576.
3. Bäckman, P., Olsson, B., Pitfalls in understanding local exposure. Dalby, R.N., Byron, P.R., Peart, J., Farr, S.J., Suman, J.D., Young, P.M., Traini, D., (eds.) Respiratory Drug Delivery 2016, vol. 1, 2016, Davis Healthcare International Publishing LLC, River Grove, 125–132.
4. Bäckman, P., Tehler, U., Olsson, B., Predicting exposure after oral inhalation of the selective glucocorticoid receptor modulator, AZD5423, based on dose, deposition pattern, and mechanistic modelling of pulmonary disposition. J. Aerosol Med. Pulm. Drug Deliv. 30:2 (2017), 108–117.
5. Bäckström, E., Lundqvist, A., Boger, E., Svanberg, P., Ewing, P., Hammarlund-Udenaes, M., Fridén, M., Development of a novel lung slice methodology for profiling of inhaled compounds. J. Pharm. Sci. 105:2 (2016), 838–845, 10.1002/jps.24575.
6. Bartels, C., Looby, M., Sechaud, R., Kaiser, G., Determination of the pharmacokinetics of glycopyrronium in the lung using a population pharmacokinetic modelling approach. Br. J. Clin. Pharmacol. 76:6 (2013), 868–879.
7. Boger, E., Evans, N., Chappell, M., Lundqvist, A., Ewing, P., Wigenborg, A., Fridén, M., Systems pharmacology approach for prediction of pulmonary and systemic pharmacokinetics and receptor occupancy of inhaled drugs. CPT Pharmacometrics Syst. Pharmacol. 5 (2016), 201–210.
8. Boisson, M., Jacobs, M., Grégoire, N., Gobin, P., Marchand, S., Couet, W., Mimoz, O., Comparison of intrapulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and colistin after aerosol delivery and intravenous administration of CMS in critically ill patients. Antimicrob. Agents Chemother. 58:12 (2014), 7331–7339.
9. Bondesson, E., Bengtsson, T., Nilsson, L.-E., Wollmer, P., Site of deposition and absorption of an inhaled hydrophilic solute. Br. J. Clin. Pharmacol. 63:6 (2007), 722–733.
10. Borghardt, J.M., Weber, B., Staab, A., Kloft, C., Pharmacometric models for characterizing the pharmacokinetics of orally inhaled drugs. AAPS J. 17 (2015), 853–870.
11. Borghardt, J.M., Weber, B., Staab, A., Kunz, C., Formella, S., Kloft, C., Investigating pulmonary and systemic pharmacokinetics of inhaled olodaterol in healthy volunteers using a population pharmacokinetic approach. Br. J. Clin. Pharmacol. 81:3 (2016), 538–552.
12. Borghardt, J.M., Weber, B., Staab, A., Kunz, C., Kloft, C., Model-based evaluation of pulmonary pharmacokinetics in asthmatic and COPD patients after oral olodaterol inhalation. Br. J. Clin. Pharmacol. 82:3 (2016), 739–753.
13. Brutche, M.H., Carlen Brutche, I., Munavvar, M., Langley, S.J., Masterson, C.M., Daley-Yates, P.T., Brown, R., Custovic, A., Woodcock, A., Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate on patients with asthma and healthy volunteers: a random crossover study. Lancet 356 (2001), 556–561.
14. Burnell, P., Asking, L., Borgström, L., Nichols, S.C., Olsson, B., Prime, D., Shrubbs, I., Studies of the human oropharyngeal airspaces using magnetic resonance imaging IV—the oropharyngeal retention effect for four inhalation delivery systems. J. Aerosol Med. Pulm. Drug Deliv. 20:3 (2007), 269–281.
15. Cabal, A., Jajamovich, G., Mehts, K., Guo, P., Przekwas, A., In-silico lung modelling platform for inhaled drig delivery. Drug Deliv. Lungs 27 (2016), 82–86.
16. Campbell, J., Van Landingham, C., Crowell, S., Gentry, R., Kaden, D., Fiebelkorn, S., Loccisano, A., Clewell, H., A preliminary regional PBPK model of lung metabolism for improving species dependent descriptions of 1,3-butadiene and its metabolites. Chem. Biol. Interact. 5:238 (2015), 102–110.
17. Caniga, M., Cabal, A., Mehta, K., Ross, D.S., Gil, M.A., Woodhouse, J.D., Eckman, J., Naber, J.R., Callahan, M.K., Goncalves, L., Hill, S.E., Mcleod, R.L., McIntosh, F., Freke, M.C., Visser, S.A.G., Johnson, N., Salmon, M., Cicmil, M., Preclinical experimental and mathematical approaches for assessing effective doses of inhaled drugs, using mometasone to support human dose predictions. J. Aerosol Med. Pulm. Drug Deliv. 29 (2016), 362–377.
18. Collingwood, S.P., Coe, D., Pryde, D., Lock, R., Respiratory drug discovery, current developments and future challenges: highlights from the society of medicines research symposium. Held on June 14th 2012 – Horsham, UK. Drugs Future 37:8 (2012), 619–625.
19. Cooper, A., Potter, T., Luker, T., Prediction of efficacious inhalation lung doses via the use of in silico lung retention quantitative structure-activity relationship models and in vitro potency screens. Drug Metab. Dispos. 38 (2010), 2218–2225.
20. Cooper, A.E., Ferguson, D., Grime, K., Optimisation of DMPK by the inhaled route: challenges and approaches. Curr. Drug Metab. 13 (2012), 457–473.
21. Danhof, M., deLange, E.C.M., Pasqua, O.E.D., Ploeger, B.A., Voskuyl, R.A., Mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) modelling in translational drug research. Trends Pharmacol. Sci. 29 (2008), 186–191.
22. Das, S.C., Stewart, P.J., The influence of lung surfactant liquid crystalline nanostructures on respiratory drug delivery. Int. J. Pharm. 514:2 (2016), 465–474.
23. Davies, N.M., Feddah, M.R., A novel method for assessing dissolution of aerosol inhaler products. Int. J. Pharm. 255 (2003), 175–187.
24. De Backer, J., Vos, W., Vinchurkar, S., Van Holsbeke, C., Poli, G., Claes, R., Salgado, R., De Backer, W., The effects of extrafine beclomethasone/formoterol (BDP/F) on lung function, dyspnoea, hyperinflation, and airway geometry in COPD patients: novel insight using functional respiratory imaging. J. Aerosol Med. Pulm. Drug Deliv. 28 (2015), 88–99.
25. DeHaan, W.H., Finlay, W.H., In vitro monodisperse aerosol deposition in a mouth and throat with six different inhalation devices. J. Aerosol Med. Pulm. Drug Deliv. 14:3 (2001), 361–367.
26. Dekhuijzen, R.P.N., Anti-inflammatory drug targeting in asthma. Should inhaled corticosteroids reach the small airways?. Curr. Drug. Ther. 7:4 (2012), 248–254.
27. Delvadia, R.R., Longest, P.W., Byron, P.R., In vitro tests for aerosol deposition. I: scaling a physical model of the upper airways to predict drug deposition variation in normal humans. J. Aerosol Med. Pulm. Drug Deliv. 25:1 (2012), 32–40.
28. Delvadia, R.R., Wei, X., Longest, P.W., Venitz, J., Byron, P.R., In vitro tests for aerosol deposition. IV:simulating variations in human breath profiles for realistic DPI testing. J. Aerosol Med. Pulm. Drug Deliv. 29:2 (2016), 196–206.
29. Doan, T.V., Grégoire, N., Lamarche, I., Gobin, P., Marchand, S., Couet, W., Olivier, J.C., A preclinical pharmacokinetic modeling approach to the biopharmaceutical characterization of immediate and microsphere-based sustained release pulmonary formulations of rifampicin. Eur. J. Pharm. Sci. 48:1–2 (2013), 223–230.
30. Donnelley, M., Morgan, K.S., Siu, K.K.W., Fouras, A., Farrow, N.G., Carnibella, R.P., Parsons, D.W., Tracking extended mucociliary transport activity of individual deposited particles: longitudinal synchrotron X-ray imaging in live mice. J. Synchrotron Radiat. 21 (2014), 768–773.
31. Donnelley, M., Morgan, K.S., Siu, K.K.W., Farrow, N.G., Stahr, C.S., Boucher, R.C., Fouras, A., Parsons, D.W., Non-invasive airway health assessment: synchrotron imaging reveals effects of hydrating treatments on mucociliary transit in vivo. Sci. Rep., 4, 2014, 3689, 10.1038/srep03689.
32. Donnelley, M., Morgan, K.S., Awadalla, M., Farrow, N.R., Hall, Chris, Parsons, D.W., High-resolution mucociliary transport measurement in live excised large animal trachea using synchrotron X-ray imaging. Respir. Res., 18(95), 2017, 10.1186/s12931-017-0573-2.
33. Edwards, C.d., Luscombe, C., Eddershaw, P., Hessel, E.M., Development of a novel quantitative structure-activity relationship model to accurately predict pulmonary absorption and replace routine use of the isolated perfused respiring rat lung model. Pharm. Res. 33 (2016), 2604–2616.
34. Ehrhardt, C., Kneuer, C., Fiegel, J., Hanes, J., Schaefer, U., Kim, Kwang-Jin, Lehr, C.-M., Influence of apical fluid volume on the development of functional intercellular junctions in the human epithelial cell line 16HBE14o-: implications for the use of this cell line as an in vitro model for bronchial drug absorption studies. Cell Tissue Res. 308 (2002), 391–400.
35. Ehrhardt, C., Bäckman, P., Couet, W., Edwards, C., Forbes, B., Friden, M., Gumpleton, M., Hosoya, K.-I., Kato, Y., Nakanishi, T., Takano, M., Terasaki, T., Yumoto, R., Current progress toward a better understanding of drug disposition within the lungs: summary proceedings of the 1st Workshop on Drug Transporters in the Lungs. J. Pharm. Sci., 2017, 10.1016/j.xphs.2017.04.011.
36. Eissing, T., Kuepfer, L., Becker, C., Block, M., Coboeken, K., Gaub, T., Goerlitz, L., Jaeger, J., Loosen, R., Ludewig, B., Meyer, M., Niederalt, C., Sevestre, M., Siegmund, H.-U., Solodenko, J., Thelen, K., Telle, U., Weiss, W., Wendl, T., Willmann, S., Lippert, J., A computational systems biology software platform for multiscale modeling and simulation: integrating whole-body physiology, disease biology, and molecular reaction networks. Front. Physiol. 2:4 (2011), 1–10.
37. Finlay, W.H., Martin, R.H., Recent advances in predictive understanding of respiratory tract deposition. J. Aerosol Med. Pulm. Drug Deliv. 21:2 (2008), 189–205.
38. Forbes, B., Ehrhardt, C., Human respiratory epithelial cell culture for drug delivery applications. Eur. J. Pharm. Biopharm. 60 (2005), 193–205.
39. Forbes, B., Shah, A., Martin, G.P., Lansley, A.B., The human bronchial epithelial cell line 16HBE140- as a model system of the airways for studying drug transport. Int. J. Pharm. 257 (2003), 161–167.
40. Forbes, B., Asgharian, B., Dailey, L.A., Ferguson, D., Gerde, P., Gumbleton, M., Hardy, C., Hassall, D., Gustavsson, L., Jones, R., Lock, R., Maas, J., McGoverin, T., Pitcairn, G., Somers, G., Wolff, R., Challenges in inhaled product development and opportunities for open innovation. Adv. Drug Deliv. Rev. 63 (2011), 69–87.
41. Forbes, B., Bäckman, P., Christopher, D., Dolovich, M., Bing, L., Morgan, B., In vitro testing for orally inhaled products: developments in science-based regulatory approaches. AAPS J. 17 (2015), 837–852.
42. Frohlich, E., Mercuri, A., Wu, S.Q., Salar-Behzadi, S., Measurements of deposition, lung surface area and lung fluid for simulation of inhaled compounds. Front. Pharmacol., 7, 2016 (Article Number 181).
43. Gaspar, M.C., Grégoire, N., Sousa, J.J., Pais, A.A., Lamarche, I., Gobin, P., Olivier, J.C., Marchand, S., Couet, W., Pulmonary pharmacokinetics of levofloxacin in rats after aerosolization of immediate-release chitosan or sustained-release PLGA microspheres. Eur. J. Pharm. Sci. 93 (2016), 184–191.
44. Gauhua, L., Wedagedera, J., Small, B.G., Almond, L., Romero, K., Hermann, D., Hanna, D., Jamei, M., Gardener, I., Development of a multicompartment permeability-limited lung PBPK model and its application on predicting pulmonary pharmacokinetics of anti-tuberculosis drugs. CPT Phaermacometrics Syst. Pharmacol. 4 (2015), 605–613.
45. Gerde, P., Malmlöf, M., Havsborn, L., Sjöberg, C.O., Ewing, P., Eirefelt, S., Ekelund, K., DissolvIt: an in vitro method for simulating the dissolution and absorption of inhaled dry powder drugs in the lungs. Assay Drug Dev. Technol. 15:2 (2017), 77–88 (ISSN: 1557-8127).
46. Giorgetti, M., Studies on the Mucin-binding of Inhaled Drug Molecules. 2016, University of East Anglia, UK (PhD Thesis).
47. Gontijo, A.V., Brillault, J., Grégoire, N., Lamarche, I., Gobin, P., Couet, W., Marchand, S., Biopharmaceutical characterization of nebulized antimicrobial agents in rats: 1. Ciprofloxacin, moxifloxacin, and grepafloxacin. Antimicrob. Agents Chemother. 58:7 (2014), 3942–3949.
48. Gontijo, A.V., Grégoire, N., Lamarche, I., Gobin, P., Couet, W., Marchand, S., Biopharmaceutical characterization of nebulized antimicrobial agents in rats: 2. Colistin. Antimicrob. Agents Chemother. 58:7 (2014), 3950–3956.
49. Grainger, C., Greenwell, L.L., Lockley, D.J., Martin, G.P., Forbes, B., Culture of Calu-3 cells at the air-liquid interface provides a representative model of the airway epithelial barrier. Pharm. Res. 23 (2006), 1482–1490.
50. Grainger, C., Saunders, M., Buttini, F., Telford, R., Martin, G.P., Jones, S.A., Forbes, B., Critical characteristics for corticosteroid solution metered dose inhaler bioequivalence. Mol. Pharm. 9 (2012), 563–569.
51. Grießinger, J., Dünnhaupt, S., Cattoz, B., Griffiths, P., Oh, S., Borrós i Gómez, S., Wilcox, M., Pearson, J., Gumbleton, M., Abdulkarim, M., Pereira de Sousa, I., Bernkop-Schnürch, A., Methods to determine the interactions of micro- and nanoparticles with mucus. Eur. J. Pharm. Biopharm. 96 (2015), 464–476.
52. Hastedt, J.E., Bäckman, P., Clark, A.R., Doub, W., Hickey, A., Hochhaus, G., Kuehl, P.J., Lehr, C.-M., Mauser, P., McConville, J., Niven, R., Sakagimi, M., Weers, J.G., Scope and relevance of a pulmonary biopharmaceutical classification system AAPS/FDA/USP Workshop March 16–17th. AAPS Open 2 (2016), 1–20.
53. Hoffman, W., Asgharian, B., The effect of lung structure on mucociliary clearance and particle retention in human and rat lungs. Toxicol. Sci. 73 (2003), 448–456.
54. ICRP, Human respiratory tract model for radiological protection. International Commission on Radiological Protection, ICRP Publication 66, 1994, Elsevier Science, Tarrytown, NY.
55. Jones, R.M., Harrison, A., A new methodology for predicting human pharmacokinetics for inhaled drugs from oratracheal pharmacokinetic data in rats. Xenobiotica 42 (2012), 75–85.
56. Korzekwa, K., Nagar, S., On the nature of physiologically-based pharmacokinetic models–a priori or a posteriori? mechanistic or empirical?. Pharm. Res. 34 (2017), 529–534.
57. Lombry, C., Edwards, D.A., Préat, V., Vanbever, R., Alveolar macrophages are a primary barrier to pulmonary absorption of macromolecules. Am. J. Phys. Lung Cell. Mol. Phys. 286:5 (2004), L1002–1008.
58. Longest, P.W., Tian, T.G., Khajeh-Hosseini-Dalasm, N., Hindle, M., Validating whole-airway CFD predictions of DPI aerosol deposition at multiple flow rates. J. Aerosol Med. Pulm. Drug Del. 29:6 (2016), 461–481.
59. Manford, F., Tronde, A., Jeppsson, A.B., Patel, N., Johansson, F., Forbes, B., Drug permeability in 16HBE14o- airway cell layers correlates with absorption from the rat lung. Eur. J. Pharm. Sci. 26 (2005), 215–220.
60. Marchand, S., Frasca, D., Dahyot-Fizelier, C., Breheret, C., Mimiz, O., Couet, W., Lung microdialysis study of levofloxacin in rats following intravenous infusion at steady state. Antimicrob. Agents Chemother. 52:9 (2008), 3074–3077.
61. Marchand, S., Grégoire, N., Brillault, J., Lamarche, I., Gobin, P., Couet, W., Biopharmaceutical characterization of nebulized antimicrobial agents in rats: 3. Tobramycin. Antimicrob. Agents Chemother. 59:10 (2015), 6646–6647.
62. Marchand, S., Chauzy, A., Dahyot-Fizelier, C., Couet, W., Microdialysis as a way to measure antibiotics concentration in tissues. Pharmacol. Res. 111 (2016), 201–207.
63. Marchand, S., Grégoire, N., Brillault, J., Lamarche, I., Gobin, P., Couet, W., Biopharmaceutical characterization of nebulized antimicrobial agents in rats. 4. Aztreonam. Antimicrob. Agents Chemother. 60:5 (2016), 3196–3198.
64. Mathias, N.R., Timoszyk, J., Stetsko, P.I., Megill, J.R., Smith, R.L., Wall, D.A., Permeability characteristics of Calu-3 human bronchial epithelial cells: in vitro-in vivo correlation to predict lung absorption in rats. J. Drug Target. 10 (2002), 31–40.
65. May, S., Jensen, B., Weiler, C., Wolkenhauer, M., Schneider, M., Lehr, C.M., Dissolution testing of powders for inhalation: influence of particle deposition and modelling of dissolution profiles. Pharm. Res. 31 (2014), 3211–3224.
66. Melin, J., Prothon, S., Kloft, C., Cleton, A., Amilon, C., Jorup, C., Bäckman, P., Olsson, B., Wählby Hamrén, U., Pharmacokinetics of the inhaled selective glucocorticoid receptor modulator AZD5423 following inhalation using different devices. AAPS J., 2017, 10.1208/s12248-016-0042-8.
67. Miller-Larson, A., Mattson, H., Hjertberg, E., Dahlbäck, M., Tunek, A., Reversible fatty acid conjugation of budesonide. Novel mechanism for prolonged retention of topically applied steroid in airway tissue. Drug Metab. Dispos. 26 (1998), 623–630.
68. Mimetikos AB, Preludium™. http://www.emmace.se/mimetikos-preludium/. (Accessed 18 May 2017)
69. Nickel, S., Clerkin, C.G., Selo, M.A., Ehrhardt, C., Transport mechanisms at the pulmonary mucosa: implications for drug delivery. Expert Opin. Drug Deliv. 13:5 (2016), 667–690.
70. Niven, R., Modulating the pharmacokinetics of inhaled drugs. Hickey, A.J., (eds.) Pharmaceutical Aerosol Technology Edition 2, 2004.
71. Olsson, B., Bäckman, P., Mouth-throat models for realistic in vitro testing: a proposal for debate. Dalby, R., Byron, P., Peart, J., Suman, J., Farr, S., Young, P., (eds.) Respiratory Drug Delivery 2014, vol. 1, 2014, DHI Publishing, River Grove, IL, 287–294.
72. Olsson, B., Bondesson, E., Borgstrom, L., Edsbacker, S., Eirefelt, S., Ekelund, K., Gustavsson, L., Hegelung-Myrback, Pulmonary drug metabolism, clearance and absorption. Smyth, H.D.C., Hickey, A.J., (eds.) Controlled Pulmonary Drug Delivery, 2011, Springer.
73. Olsson, B., Borgström, L., Lundbäck, H., Svensson, M., Validation of a general in vitro approach for prediction of total lung deposition in healthy adults for pharmaceutical inhalation products. J. Aerosol Med. Pulm. Drug Deliv. 23 (2013), 355–369.
74. O'Riordan, T.G., Zwang, J., Smaldone, G.C., Mucociliary clearance in adult asthma. Am. Rev. Resp. Dis. 146:3 (1992), 598–603.
75. Pang, Y.N., Sakagami, M., Byron, P.R., The pharmacokinetics of pulmonary insulin in the in vitro isolated perfused rat lung: implications of metabolism and regional deposition. Eur. J. Pharm. Sci. 25 (2005), 369–378.
76. PK-SIM™ Computational Systems Biology: Bayer AG. http://www.systems-biology.com/products/PK-Sim.html. (Accessed 30 May 2017)
77. Riley, T., Christopher, D., Arp, J., Casazza, A., Colombani, A., Cooper, A., Dey, M., Maas, J., Mitchell, J., Reiners, M., Sogari, N., Tougas, T., Lyapustina, S., Challenges with developing in vitro dissolution tests for orally Inhaled Products (OIPs). AAPS PharmSciTech 13:3 (2012), 978–989.
78. Rodvold, K.A., Yoo, L., andGeorge, J.M., Penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antifungal, antitubercular and miscellaneous anti-infective agents. Clin. Pharmacokinet. 50:11 (2011), 689–704.
79. Ruparelia, P., Cheow, H.K., Evans, J.W., Banney, L., Shankar, S., Szczepura, K.R., Swift, A.E., Ballinger, J.R., Hartman, N.G., Chilvers, E.R., Peters, A.M., Pulmonary elimination rate of inhaled 99mTc-sestamibi radioaerosol is delayed in healthy cigarette smokers. Br. J. Clin. Pharmacol. 65:4 (2008), 611–614.
80. Schum, M., Yeh, H., Theoretical evaluation of aerosol deposition in anatomical models of mammalian lung airways. Bull. Math. Biol. 42 (1980), 1–15.
81. SimCyp Simulator™. https://www.certara.com/software/physiologically-based-pharmacokinetic-modeling-and-simulation/simcyp-simulator/absorption/. (Accessed 18 May 2017)
82. Somers, G.I., Lindsay, N., Lowdon, B.M., Jones, A.E., Freathy, C., Ho, S., Woodrooffe, A.J.M., Bayliss, M.K., Manchee, G.R., A comparison of the expression and metabolizing activities of phase I and II enzymes in freshly isolated human lung parenchymal cells and cryopreserved human hepatocytes. Drug Metab. Dispos. 35 (2007), 1797–1805.
83. Son, Y.-J., McConville, J.T., Development of a standardized dissolutiontest method for inhaled pharmaceutical formulations. Int. J. Pharm. 382 (2009), 15–22.
84. Stass, H., Baumann-Noss, S., Delesen, H., Nagelschmitz, J., Willmann, S., Edginton, A., Ciprofloxacin Pulmosphere Inhalation Powder: A Healthy Volounteeer Study. 2008, ATS, Toronto (Poster).
85. Stass, H., Nagelschmitz, J., Willmann, S., Delesen, H., Gupta, A., Baumann, S., Inhalation of a dry powder ciprofloxacin formulation in healthy subjects: a phase I study. Clin. Drug Investig. 33 (2013), 419–427.
86. Torres, B.G.S., Helfer, V.E., Bernardes, P.M., Macedo, A.J., Nielsen, E.I., Friberg, L.E., dalla Costa, T., Population pharmacokinetic modelling as a tool to characterize the decrease in ciprofloxacin free intestinal levels caused by pseudomonas aeruginosa biofilm lung infection in wistar rats. Antimicrob. Agents Chemother., 61(7), 2017, 10.1128/AAC.02553-16.
87. Tronde, A., Nordén, B., Marchner, H., Wendel, A.-K., Lennernäs, H., Bengtsson, U.H., Pulmonary absorption rate and bioavailability of drugs in vivo in rats: structure-absorption relationships and physicochemical profiling of inhaled drugs. J. Pharm. Sci. 92 (2003), 1216–1233.
88. Tronde, A., Nordén, B., Jeppsson, A.B., Brunmark, P., Nilsson, E., Lennernäs, H., Bengtsson, U.H., Drug absorption from the isolated perfused rat lung-correlations with drug physico-chemical properties and epithelial permeability. J. Drug Target. 11 (2003), 61–74.
89. Tronde, A., Bosquillon, C., Forbes, B., The isolated perfused lung for drug absorption studies. Ehrhardt, C., Kim, K.J., (eds.) Drug Absorption Studies: In Situ, In Vitro and In Silico Models, 2008, Springer, New York, 135–163.
90. Ufuk, A., Assmus, F., Francis, l., Plumb, J., Damian, V., Gertz, M., Houston, J.B., Galetin, A., In vitro and in silico tools to assess extent of cellular uptake and lysosomal sequestration of respiratory drugs in human alveolar macrophages. Mol. Pharm. 14 (2017), 1033–1046.
91. Usmani, O.S., Biddiscombe, M.F., Barnes, P.J., Regional lung deposition and bronchodilator response as a function of _2-agonist particle size. Am. J. Respir. Crit. Care Med. 172 (2005), 1497–1504.
92. Velaga, S.P., Djuris, J., Cvijic, S., Rozou, S., Russo, P., Colombo, G., Rossi, A., Dry powder inhalers: an overview of the in vitro dissolution methodologies and their correlation with the biopharmaceutical aspects of the drug products. Eur. J. Pharm. Sci., 2017, 10.1016/j.ejps.2017.09.002.
93. Wang, Y.-B., Watts, A.B., Peters, J.I., Williams, R.O. III, The impact of pulmonary diseases on the fate of inhaled medicines—a review. Int. J. Pharm. 461 (2014), 112–128.
94. Wei, X., Byron, P.R., Longest, W.P., Predicting variation in lung dose with different mouth-throat models. Dalby, R., Byron, P., Peart, J., Suman, J., Farr, S., Young, P., (eds.) Respiratory Drug Delivery 2014, vol. 3, 2014, DHI Publishing, River Grove, 773–776.
95. Weibel, E.R., Morphometry of the Human Lung. 1963, Springer, Berlin.
96. Yu, J.Y., Rosania, G.R., Cell-based multiscale computational modeling of small molecule absorption and retention in the lungs. Pharm. Res. 27 (2010), 457–467.
97. Zhou, Y., Sun, J.J., Cheng, Y.S., Comparison of deposition in the USP and physical mouth-throat models with solid and liquid particles. J. Aerosol Med. Pulm. Drug Deliv. 24 (2011), 277–284.
98. Zhuang, X., Lu, C., PBPK modeling and simulation in drug research and development. Acta Pharm. Sin. B 6:5 (2016), 430–440.
99. Zimmermann, E.S., Laureano, J.V., dos Santos, C.N., Schmidt, S., Lagishetty, C.V., de Castro, V.W., dalla Costa, T., Simultaneous semimechanistic population analysis of levofloxacin in plasma, lung and prostate to describe the influence of efflux transporters on drug distribution following intravenous and intratracheal administration. Antimicrob. Agents Chemother. 60:2 (2015), 946–954.