Pharmacokinetic/pharmacodynamic approaches to drug delivery design for inhalation drugs

References

• Biddiscombe MF, Usmani OS. Is there room for further innovation in inhaled therapy for airways disease? Breathe (Sheff). 2018;14(3):216–224.
   PubMedGoogle Scholar
• Keshavarz A, Kadry H, Alobaida A, et al. Newer approaches and novel drugs for inhalational therapy for pulmonary arterial hypertension. Expert Opin Drug Deliv. 2020;17(4):439–461.
   PubMed Web of Science ®Google Scholar
• Cazzola M, Stolz D, Rogliani P, et al. α1-Antitrypsin deficiency and chronic respiratory disorders. Eur Respir Rev. 2020;29(155):190073.
   PubMed Web of Science ®Google Scholar
• Antoniu SA. Investigational inhaled therapies for non-CF bronchiectasis. Expert Opin Investig Drugs. 2018;27(2):139–146.
   PubMed Web of Science ®Google Scholar
• Berlinski A. 2019 year in review: aerosol therapy. Respir Care. 2020;65(5):705–712.
   PubMed Web of Science ®Google Scholar
• Sécher T, Mayor A, Heuzé-Vourc’h N. Inhalation of immuno-therapeutics/-prophylactics to fight respiratory tract Infections: an appropriate drug at the right place! Front Immunol. 2019;10:2760.
   PubMed Web of Science ®Google Scholar
• Lee WH, Loo CY, Ghadiri M, et al. The potential to treat lung cancer via inhalation of repurposed drugs. Adv Drug Deliv Rev. 2018;133:107–130.
   PubMed Web of Science ®Google Scholar
• Liu H, Shan X, Yu J, et al. Recent advances in inhaled formulations and pulmonary insulin delivery systems. Curr Pharm Biotechnol. 2020;21(3):180–193.
   PubMed Web of Science ®Google Scholar
• Stapleton KW. Orally inhaled migraine therapy: where are we now? Adv Drug Deliv Rev. 2018;133:131–134.
   PubMed Web of Science ®Google Scholar
• Teutonico D, Montanari S, Ponchel G. Leuprolide acetate: pharmaceutical use and delivery potentials. Expert Opin Drug Deliv. 2012;9(3):343–354.
   PubMed Web of Science ®Google Scholar
• Borghardt JM, Kloft C, Sharma A. Inhaled therapy in respiratory disease: the complex interplay of pulmonary kinetic processes. Can Respir J. 2018;2018:2732017.
   PubMed Web of Science ®Google Scholar
• Loira-Pastoriza C, Todoroff J, Vanbever R. Delivery strategies for sustained drug release in the lungs. Adv Drug Deliv Rev. 2014;75:81–91.
   PubMed Web of Science ®Google Scholar
• Newman SP. Delivering drugs to the lungs: the history of repurposing in the treatment of respiratory diseases. Adv Drug Deliv Rev. 2018;133:5–18.
   PubMed Web of Science ®Google Scholar
• Sou T, Bergström CAS. Contemporary formulation development for inhaled pharmaceuticals. J Pharm Sci. 2020;110:66–86.
   PubMed Web of Science ®Google Scholar
• Ibrahim M, Garcia-Contreras L. Preclinical pharmacokinetics of antitubercular drugs. In: Hickey AJ, editor. Delivery systems for tuberculosis prevention and treatment. West Sussex, UK: John Wiley & Sons, Ltd; 2016. p. 131–155.
   Google Scholar
• Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol. 2003;56(6):588–599.
   PubMed Web of Science ®Google Scholar
• Kukut Hatipoglu M, Hickey AJ, Garcia-Contreras L. Pharmacokinetics and pharmacodynamics of high doses of inhaled dry powder drugs. Int J Pharm. 2018;549(1–2):306–316.
   PubMedGoogle Scholar
• Kourmatzis A, Cheng S, Chan HK. Airway geometry, airway flow, and particle measurement methods: implications on pulmonary drug delivery. Expert Opin Drug Deliv. 2018;15(3):271–282.
   PubMed Web of Science ®Google Scholar
• Newman SP. Aerosols. In: Laurent GJ, Shapiro SD, editors. Encyclopedia of respiratory medicine. Amsterdam: Elsevier Limited; 2006. p. 58–64.
   Google Scholar
• Roy I, Vij N. Nanodelivery in airway diseases: challenges and therapeutic applications. Nanomedicine. 2010;6(2):237–244.
   PubMed Web of Science ®Google Scholar
• Edsbäcker S, Wollmer P, Selroos O, et al. Do airway clearance mechanisms influence the local and systemic effects of inhaled corticosteroids? Pulm Pharmacol Ther. 2008;21(2):247–258.
   PubMed Web of Science ®Google Scholar
• Ehrhardt C, Bäckman P, Couet W, et al. Current progress toward a better understanding of drug disposition within the lungs: summary proceedings of the first workshop on drug transporters in the lungs. J Pharm Sci. 2017;106(9):2234–2244.
   PubMed Web of Science ®Google Scholar
• Winkler J, Hochhaus G, Derendorf H. How the lung handles drugs: pharmacokinetics and pharmacodynamics of inhaled corticosteroids. Proc Am Thorac Soc. 2004;1(4):356–363.
   PubMedGoogle Scholar
• Miravitlles M, Soler-Cataluña JJ, Alcázar B, et al. Factors affecting the selection of an inhaler device for COPD and the ideal device for different patient profiles. Results of EPOCA Delphi consensus. Pulm Pharmacol Ther. 2018;48:97–103.
   PubMed Web of Science ®Google Scholar
• Chandel A, Goyal AK, Ghosh G, et al. Recent advances in aerosolised drug delivery. Biomed Pharmacother. 2019;112:108601.
   PubMed Web of Science ®Google Scholar
• Cazzola M, Cavalli F, Usmani OS, et al. Advances in pulmonary drug delivery devices for the treatment of chronic obstructive pulmonary disease. Expert Opin Drug Deliv. 2020;17(5):635–646.
   PubMed Web of Science ®Google Scholar
• Rogliani P, Calzetta L, Coppola A, et al. Optimizing drug delivery in COPD: the role of inhaler devices. Respir Med. 2017;124:6–14.
   PubMed Web of Science ®Google Scholar
• Maes A, DePetrillo P, Siddiqui S, et al. Pharmacokinetics of co-suspension delivery technology budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF MDI) and budesonide/formoterol fumarate dihydrate (BFF MDI) fixed-dose combinations compared With an active control: a phase 1, randomized, single-dose, crossover study in healthy adults. Clin Pharmacol Drug Dev. 2019;8(2):223–233.
   PubMed Web of Science ®Google Scholar
• Matera MG, Rinaldi B, Calzetta L, et al. Pharmacokinetics and pharmacodynamics of inhaled corticosteroids for asthma treatment. Pulm Pharmacol Ther. 2019;58:101828.
   PubMed Web of Science ®Google Scholar
• Hohlfeld JM, Sharma A, van Noord JA, et al. Pharmacokinetics and pharmacodynamics of tiotropium solution and tiotropium powder in chronic obstructive pulmonary disease. J Clin Pharmacol. 2014;54(4):405–414.
   PubMed Web of Science ®Google Scholar
• Ferrati S, Wu T, Kanapuram SR, et al. Dosing considerations for inhaled biologics. Int J Pharm. 2018;549(1–2):58–66.
   PubMedGoogle Scholar
• Osman N, Kaneko K, Carini V, et al. Carriers for the targeted delivery of aerosolized macromolecules for pulmonary pathologies. Expert Opin Drug Deliv. 2018;15(8):821–834.
   PubMed Web of Science ®Google Scholar
• Derendorf H, Lesko LJ, Chaikin P, et al. Pharmacokinetic/pharmacodynamic modeling in drug research and development. J Clin Pharmacol. 2000;40(12 Pt 2):1399–1418.
   PubMed Web of Science ®Google Scholar
• Padden J, Skoner D, Hochhaus G. Pharmacokinetics and pharmacodynamics of inhaled glucocorticoids. J Asthma. 2008;45(Suppl 1):13–24.
   PubMed Web of Science ®Google Scholar
• Pilcer G, Wauthoz N, Amighi K. Lactose characteristics and the generation of the aerosol. Adv Drug Deliv Rev. 2012;64(3):233–256.
   PubMed Web of Science ®Google Scholar
• Cooper AE, Ferguson D, Grime K. Optimisation of DMPK by the inhaled route: challenges and approaches. Curr Drug Metab. 2012;13(4):457–473.
   PubMed Web of Science ®Google Scholar
• Cazzola M, Testi R, Matera MG. Clinical pharmacokinetics of salmeterol. Clin Pharmacokinet. 2002;41(1):19–30.
   PubMed Web of Science ®Google Scholar
• Corcoran TE. Imaging in aerosol medicine. Respir Care. 2015;60(6):850–855.
   PubMed Web of Science ®Google Scholar
• Eberl S, Chan HK, Daviskas E. SPECT Imaging for radioaerosol deposition and clearance studies. J Aerosol Med. 2006;19(1):8–20.
   PubMedGoogle Scholar
• Dolovich M, Hahmias C, Coates G, et al. Unleashing the PET: 3D imaging of the lung. In: Dalby RN, Byron PR, Farr SJ, editors. Respiratory drug delivery VII. Raleigh: Serentec Press; 2000. p. 215–230.
   Google Scholar
• Newman S, Fleming J. Challenges in assessing regional distribution of inhaled drug in the human lungs. Expert Opin Drug Deliv. 2011;8(7):841–855.
   PubMed Web of Science ®Google Scholar
• Yang MY, Chan JG, Chan HK. Pulmonary drug delivery by powder aerosols. J Control Release. 2014;193:228–240.
   PubMed Web of Science ®Google Scholar
• Khoubnasabjafari M, Rahimpour E, Samini M, et al. A new hypothesis to investigate bioequivalence of pharmaceutical inhalation products. Daru. 2019;27(1):517–524.
   PubMed Web of Science ®Google Scholar
• Kruizinga MD, Birkhoff WAJ, van Esdonk MJ, et al. Pharmacokinetics of intravenous and inhaled salbutamol and tobramycin: an exploratory study to investigate the potential of exhaled breath condensate as a matrix for pharmacokinetic analysis. Br J Clin Pharmacol. 86(1): 175–181. 2020.
   PubMed Web of Science ®Google Scholar
• Rodvold KA, George JM, Yoo L. Penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antibacterial agents. Clin Pharmacokinet. 2011;50(10):637–664.
   PubMed Web of Science ®Google Scholar
• Guillon A, Pardessus J, Lhommet P, et al. Exploring the fate of inhaled monoclonal antibody in the lung parenchyma by microdialysis. MAbs. 11(2): 297–304. 2019.
   PubMed Web of Science ®Google Scholar
• Hutschala D, Skhirtladze K, Zuckermann A, et al. In vivo measurement of levofloxacin penetration into lung tissue after cardiac surgery. Antimicrob Agents Chemother. 2005;49(12):5107–5111.
   PubMed Web of Science ®Google Scholar
• Zecchi R, Trevisani M, Pittelli M, et al. Impact of drug administration route on drug delivery and distribution into the lung: an imaging mass spectrometry approach. Eur J Mass Spectrom (Chichester). 2013;19(6):475–482.
   PubMed Web of Science ®Google Scholar
• Ehrmann S, Schmid O, Darquenne C, et al. Innovative preclinical models for pulmonary drug delivery research. Expert Opin Drug Deliv. 2020;17(4):463–478.
   PubMed Web of Science ®Google Scholar
• Bäckman P, Arora S, Couet W, et al. Advances in experimental and mechanistic computational models to understand pulmonary exposure to inhaled drugs. Eur J Pharm Sci. 2018;113:41–52.
   PubMed Web of Science ®Google Scholar
• Chrystyn H. Methods to identify drug deposition in the lungs following inhalation. Br J Clin Pharmacol. 2001;51(4):289–299.
   PubMed Web of Science ®Google Scholar
• Bäckman P, Adelmann H, Petersson G, et al. Advances in inhaled technologies: understanding the therapeutic challenge, predicting clinical performance, and designing the optimal inhaled product. Clin Pharmacol Ther. 2014;95(5):509–520.
   PubMed Web of Science ®Google Scholar
• Matera MG, Rinaldi B, Page C, et al. Pharmacokinetic considerations concerning the use of bronchodilators in the treatment of chronic obstructive pulmonary disease. Expert Opin Drug Metab Toxicol. 14(10): 1101–1111. 2018.
   PubMed Web of Science ®Google Scholar
• European Medicines Agency. Questions & answers: positions on specific question addressed to the pharmacokinetics working party (PKWP). Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002963.pdf.
   Google Scholar
• Lipworth BJ. Pharmacokinetics of inhaled drugs. Br J Clin Pharmacol. 1996;42(6):697–705.
   PubMed Web of Science ®Google Scholar
• US Food and Drug Administration. FYs 2013–2017 regulatory science report: locally-acting orally inhaled and nasal drug products. Available from: https://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/GenericDrugs/ucm592245.htm.
   Google Scholar
• Elsayed MMA, Shalash AO. Modeling the performance of carrier-based dry powder inhalation formulations: where are we, and how to get there? J Control Release. 2018;279:251–261.
   PubMed Web of Science ®Google Scholar
• Barros AS, Costa A, Sarmento B. Building three-dimensional lung models for studying pharmacokinetics of inhaled drugs. Adv Drug Deliv Rev. 2020. DOI:10.1016/j.addr.2020.09.008.
   PubMed Web of Science ®Google Scholar
• Al-Tabakha MM, Alomar MJ. In vitro dissolution and in silico modeling shortcuts in bioequivalence testing. Pharmaceutics. 2020;12(1):45.
   Web of Science ®Google Scholar
• Hofemeier P, Koshiyama K, Wada S, et al. One (sub-)acinus for all: fate of inhaled aerosols in heterogeneous pulmonary acinar structures. Eur J Pharm Sci. 2018;113:53–63.
   PubMed Web of Science ®Google Scholar
• Walenga RL, Babiskin AH, Zhao L. In silico methods for development of generic drug-device combination orally inhaled drug products. CPT Pharmacometrics Syst Pharmacol. 2019;8(6):359–370.
   PubMedGoogle Scholar
• Patton JS, Byron PR. Inhaling medicines: delivering drugs to the body through the lungs. Nat Rev Drug Discov. 2007;6(1):67–74.
   PubMed Web of Science ®Google Scholar
• Bhagwat S, Schilling U, Chen MJ, et al. Predicting pulmonary pharmacokinetics from in vitro properties of dry powder inhalers. Pharm Res. 2017;34(12):2541–2556.
   PubMed Web of Science ®Google Scholar
• Taburet AM, Schmit B. Pharmacokinetic optimisation of asthma treatment. Clin Pharmacokinet. 1994;26(5):396–418.
   PubMed Web of Science ®Google Scholar
• Matera MG, Rinaldi B, Belardo C, et al. A review of the pharmacokinetics of M3 muscarinic receptor antagonists used for the treatment of asthma. Expert Opin Drug Metab Toxicol. 2020;16(2):143–148.
   PubMed Web of Science ®Google Scholar
• Cazzola M, Page CP, Calzetta L, et al. Pharmacology and therapeutics of bronchodilators. Pharmacol Rev. 2012;64(3):450–504.
   PubMed Web of Science ®Google Scholar
• Cazzola M, Page CP, Rogliani P, et al. β2-agonist therapy in lung disease. Am J Respir Crit Care Med. 2013;187(7):690–696.
   PubMed Web of Science ®Google Scholar
• van der Velden WJC, Heitman LH, Rosenkilde MM. Perspective: implications of ligand-receptor binding kinetics for therapeutic targeting of G protein-coupled receptors. ACS Pharmacol Transl Sci. 2020;3(2):179–189.
   PubMedGoogle Scholar
• Anderson GP, Lindén A, Rabe KF. Why are long-acting beta-adrenoceptor agonists long-acting? Eur Respir J. 1994;7(3):569–578.
   PubMed Web of Science ®Google Scholar
• Anderson P, Lötvall J, Lindén A. Relaxation kinetics of formoterol and salmeterol in the guinea pig trachea in vitro. Lung. 1996;174(3):159–170.
   PubMed Web of Science ®Google Scholar
• Sykes DA, Charlton SJ. Slow receptor dissociation is not a key factor in the duration of action of inhaled long-acting β2-adrenoceptor agonists. Br J Pharmacol. 2012;165(8):2672–2683.
   PubMed Web of Science ®Google Scholar
• Salomon JJ, Hagos Y, Petzke S, et al. Beta-2 adrenergic are substrates and inhibitors of human organic cation transporter 1. Mol Pharm. 2015;12(8):2633–2641.
   PubMedGoogle Scholar
• Quinn D, Barnes CN, Yates W, et al. Pharmacodynamics, pharmacokinetics and safety of revefenacin (TD-4208), a long-acting muscarinic antagonist, in patients with chronic obstructive pulmonary disease (COPD): results of two randomized, double-blind, phase 2 studies. Pulm Pharmacol Ther. 2018;48:71–79.
   PubMed Web of Science ®Google Scholar
• Nakamura T, Nakanishi T, Haruta T, et al. Transport of ipratropium, an anti-chronic obstructive pulmonary disease drug, is mediated by organic cation/carnitine transporters in human bronchial epithelial cells: implications for carrier-mediated pulmonary absorption. Mol Pharm. 2010;7(1):187–195.
   PubMed Web of Science ®Google Scholar
• Sykes DA, Dowling MR, Leighton-Davies J, et al. The influence of receptor kinetics on the onset and duration of action and the therapeutic index of NVA237 and tiotropium. J Pharmacol Exp Ther. 2012;343(2):520–528.
   PubMed Web of Science ®Google Scholar
• Calzetta L, Matera MG, Cazzola M. Pharmacological interaction between LABAs and LAMAs in the airways: optimizing synergy. Eur J Pharmacol. 2015;761:168–173.
   PubMed Web of Science ®Google Scholar
• Calzetta L, Matera MG, Cazzola M. Pharmacological mechanisms leading to synergy in fixed-dose dual bronchodilator therapy. Curr Opin Pharmacol. 2018;40:95–103.
   PubMed Web of Science ®Google Scholar
• Calzetta L, Matera MG, Cazzola M, et al. Optimizing the development strategy of combination therapy in respiratory medicine: from isolated airways to patients. Adv Ther. 2019;36(12):3291–3298.
   PubMed Web of Science ®Google Scholar
• Lipworth BJ, Jackson CM. Safety of inhaled and intranasal corticosteroids: lessons for the new millennium. Drug Saf. 2000;23(1):11–33.
   PubMed Web of Science ®Google Scholar
• Ora J, Calzetta L, Matera MG, et al. Advances with glucocorticoids in the treatment of asthma: state of the art. Expert Opin Pharmacother. 2020;21:2305–2316.
   PubMed Web of Science ®Google Scholar
• Derendorf H, Nave R, Drollmann A, et al. Relevance of pharmacokinetics and pharmacodynamics of inhaled corticosteroids to asthma. Eur Respir J. 2006;28(5):1042–1050.
   PubMed Web of Science ®Google Scholar
• Kelly HW. Comparative potency and clinical efficacy of inhaled corticosteroids. Respir Care Clin N Am. 1999;5(4):537–553.
   PubMedGoogle Scholar
• Daley-Yates PT. Inhaled corticosteroids: potency, dose equivalence and therapeutic index. Br J Clin Pharmacol. 2015;80(3):372–380.
   PubMed Web of Science ®Google Scholar
• Rossi GA, Cerasoli F, Cazzola M. Safety of inhaled corticosteroids: room for improvement. Pulm Pharmacol Ther. 2007;20(1):23–35.
   PubMed Web of Science ®Google Scholar
• Allen DB, Bielory L, Derendorf H, et al. Inhaled corticosteroids: past lessons and future issues. J Allergy Clin Immunol. 2003;112(3 Suppl):S1–S40.
   PubMedGoogle Scholar
• Hochhau G. Pharmacokinetic and pharmacodynamic properties important for inhaled corticosteroids. Ann Allergy Asthma Immunol. 2007;98(2):S7–S15.
   Web of Science ®Google Scholar
• Wolthers OD. Extra-fine particle inhaled corticosteroids, pharmacokinetics and systemic activity in children with asthma. Pediatr Allergy Immunol. 2016;27(1):13–21.
   PubMed Web of Science ®Google Scholar
• Derendorf H, Möllmann H, Hochhaus G, et al. Clinical PK/PD modelling as a tool in drug development of corticosteroids. Int J Clin Pharmacol Ther. 1997;35(10):481–488.
   PubMed Web of Science ®Google Scholar
• Bodier-Montagutelli E, Mayor A, Vecellio L, et al. Designing inhaled protein therapeutics for topical lung delivery: what are the next steps? Expert Opin Drug Deliv. 2018;15(8):729–736.
   PubMed Web of Science ®Google Scholar
• Guilleminault L, Azzopardi N, Arnoult C, et al. Fate of inhaled monoclonal antibodies after the deposition of aerosolized particles in the respiratory system. J Control Release. 2014;196:344–354.
   PubMed Web of Science ®Google Scholar
• Lazarus RA, Wagener JS. Recombinant human deoxyribonuclease I. In: Crommelin D, Sindelar R, Meibohm B, editors. Pharmaceutical biotechnology. Cham: Springer; 2019. p. 471–488.
   Google Scholar
• Siekmeier R. Lung deposition of inhaled alpha-1-proteinase inhibitor (alpha 1-PI) - problems and experience of alpha1-PI inhalation therapy in patients with hereditary alpha1-PI deficiency and cystic fibrosis. Eur J Med Res. 2010;15(Suppl 2):164–174.
   PubMedGoogle Scholar
• Brand P, Schulte M, Wencker M, et al. Lung deposition of inhaled alpha1-proteinase inhibitor in cystic fibrosis and alpha1-antitrypsin deficiency. Eur Respir J. 2009;34(2):354–360.
   PubMed Web of Science ®Google Scholar
• Lightwood D, O’Dowd V, Carrington B, et al. The discovery, engineering and characterisation of a highly potent anti-human IL-13 fab fragment designed for administration by inhalation. J Mol Biol. 2013;425(3):577–593.
   PubMed Web of Science ®Google Scholar
• Matera MG, Calzetta L, Rogliani P, et al. Monoclonal antibodies for severe asthma: pharmacokinetic profiles. Respir Med. 2019;153:3–13.
   PubMed Web of Science ®Google Scholar
• Liang W, Pan HW, Vllasaliu D, et al. Pulmonary delivery of biological drugs. Pharmaceutics. 2020;12(11):E1025.
   PubMed Web of Science ®Google Scholar
• Burgess G, Boyce M, Jones M, et al. Randomized study of the safety and pharmacodynamics of inhaled interleukin-13 monoclonal antibody fragment VR942. EBioMedicine. 2018;35:67–75.
   PubMed Web of Science ®Google Scholar
• Respaud R, Vecellio L, Diot P, et al. Nebulization as a delivery method for mAbs in respiratory diseases. Expert Opin Drug Deliv. 2015;12(6):1027–1039.
   PubMed Web of Science ®Google Scholar
• Olsson B, Bondesson E, Borgström L, et al. Pulmonary drug metabolism, clearance, and absorption. In: Smyth HDC, A J H, editors. Controlled pulmonary drug delivery. New York: Springer; 2011. p. 21–50.
   Google Scholar
• Ulrich P, Blaich G, Baumann A, et al. Biotherapeutics in non-clinical development: strengthening the interface between safety, pharmacokinetics-pharmacodynamics and manufacturing. Regul Toxicol Pharmacol. 2018;94:91–100.
   PubMed Web of Science ®Google Scholar
• Larios Mora A, Detalle L, Gallup JM, et al. Delivery of ALX-0171 by inhalation greatly reduces respiratory syncytial virus disease in newborn lambs. MAbs. 2018;10(5):778–795.
   PubMed Web of Science ®Google Scholar
• Germani M, Niederalt C, Kanacher T, et al. A physiologically-based Pharmacokinetic (PB-PK) model to explore ALX-0171 PK in infants following inhalation. Fifth American Conference on Pharmacometrics; 2014.
   Google Scholar
• Morrison C. Nanobody approval gives domain antibodies a boost. Nat Rev Drug Discov. 2019 l;18(7):485–487.
   PubMed Web of Science ®Google Scholar
• Cunningham S, Piedra PA, Martinon-Torres F, et al. Nebulised ALX-0171 for respiratory syncytial virus lower respiratory tract infection in hospitalised children: a double-blind, randomised, placebo-controlled, phase 2b trial. Lancet Respir Med. 2020.
   Google Scholar
• Food and Drug Administration. Guidance for industry–estimating the maximum safe dose in initial clinical trials for therapeutics in adult healthy volunteers. 2005. Available from: http://www.fda.gov/downloads/Drugs/Guidances/UCM078932.pdf.
   Google Scholar
• Tibbitts J, Cavagnaro JA, Haller CA, et al. Practical approaches to dose selection for first-in-human clinical trials with novel biopharmaceuticals. Regul Toxicol Pharmacol. 2010;58(2):243–251.
   PubMed Web of Science ®Google Scholar
• Guillon A, Sécher T, Dailey LA, et al. Insights on animal models to investigate inhalation therapy: relevance for biotherapeutics. Int J Pharm. 536(1): 116–126. 2018.
   PubMedGoogle Scholar
• Röhm M, Carle S, Maigler F, et al. A comprehensive screening platform for aerosolizable protein formulations for intranasal and pulmonary drug delivery. Int J Pharm. 2017;532(1):537–546.
   PubMedGoogle Scholar
• Benam KH, Novak R, Nawroth J, et al. Matched-comparative modeling of normal and diseased human airway responses using a microengineered breathing lung chip. Cell Syst. 2016;3(5):456–466.
   PubMed Web of Science ®Google Scholar
• Okuda T, Okamoto H. Present situation and future progress of inhaled lung cancer therapy: necessity of inhaled formulations with drug delivery functions. Chem Pharm Bull (Tokyo). 2020;68(7):589–602.
   PubMed Web of Science ®Google Scholar
• Zarogoulidis P, Eleftheriadou E, Sapardanis I, et al. Feasibility and effectiveness of inhaled carboplatin in NSCLC patients. Invest New Drugs. 2012;30(4):1628–1640.
   PubMed Web of Science ®Google Scholar
• Lemarie E, Vecellio L, Hureaux J, et al. Aerosolized gemcitabine in patients with carcinoma of the lung: feasibility and safety study. J Aerosol Med Pulm Drug Deliv. 2011;24(6):261–270.
   PubMed Web of Science ®Google Scholar
• Sardeli C, Zarogoulidis P, Kosmidis C, et al. Inhaled chemotherapy adverse effects: mechanisms and protection methods. Lung Cancer Manag. 2020;8(4):LMT 19.
   Web of Science ®Google Scholar
• Abdelaziz HM, Gaber M, Abd-Elwakil MM, et al. Inhalable particulate drug delivery systems for lung cancer therapy: nanoparticles, microparticles, nanocomposites and nanoaggregates. J Control Release. 2018;269:374–392.
   PubMed Web of Science ®Google Scholar
• Youn YS, Bae YH. Perspectives on the past, present, and future of cancer nanomedicine. Adv Drug Deliv Rev. 2018;130:3–11.
   PubMed Web of Science ®Google Scholar
• Agrahari V, Agrahari V, Mitra AK. Nanocarrier fabrication and macromolecule drug delivery: challenges and opportunities. Ther Deliv. 2016;7(4):257–278.
   PubMed Web of Science ®Google Scholar
• Levet V, Merlos R, Rosière R, et al. Platinum pharmacokinetics in mice following inhalation of cisplatin dry powders with different release and lung retention properties. Int J Pharm. 2017;517(1–2):359–372.
   PubMedGoogle Scholar
• Rosière R, Berghmans T, De Vuyst P, et al. The position of inhaled chemotherapy in the care of patients with lung tumors: clinical feasibility and indications according to recent pharmaceutical progresses. Cancers (Basel). 2019;11(3):329.
   Web of Science ®Google Scholar
• Xu C, Wang Y, Guo Z, et al. Pulmonary delivery by exploiting doxorubicin and cisplatin co-loaded nanoparticles for metastatic lung cancer therapy. J Control Release. 2019;295:153–163.
   PubMed Web of Science ®Google Scholar
• Shen AM, Minko T. Pharmacokinetics of inhaled nanotherapeutics for pulmonary delivery. J Control Release. 2020;326:222–244.
   PubMed Web of Science ®Google Scholar
• Heffernan AJ, Sime FB, Lipman J, et al. Intrapulmonary pharmacokinetics of antibiotics used to treat nosocomial pneumonia caused by Gram-negative bacilli: A systematic review. Int J Antimicrob Agents. 2019;53(3):234–245.
   PubMed Web of Science ®Google Scholar
• Karampitsakos T, Papaioannou O, Kaponi M, et al. Low penetrance of antibiotics in the epithelial lining fluid. The role of inhaled antibiotics in patients with bronchiectasis. Pulm Pharmacol Ther. 2020;60:101885.
   PubMed Web of Science ®Google Scholar
• Cazzola M, Blasi F, Terzano C, et al. Delivering antibacterials to the lungs: considerations for optimizing outcomes. Am J Respir Med. 2002;1(4):261–272.
   PubMedGoogle Scholar
• Matera MG, Tufano MA, Polverino M, et al. Pulmonary concentrations of dirithromycin and erythromycin during acute exacerbation of mild chronic obstructive pulmonary disease. Eur Respir J. 1997;10(1):98–103.
   PubMed Web of Science ®Google Scholar
• Cazzola M, Matera MG, Donnarumma G, et al. Pharmacodynamics of levofloxacin in patients with acute exacerbation of chronic bronchitis. Chest. 2005;128(4):2093–2098.
   PubMed Web of Science ®Google Scholar
• Maselli DJ, Keyt H, Restrepo MI. Inhaled antibiotic therapy in chronic respiratory diseases. Int J Mol Sci. 2017;18(5):1062.
   PubMed Web of Science ®Google Scholar
• Mukker JK, Singh RS, Derendorf H. Pharmacokinetic and pharmacodynamic implications in inhalable antimicrobial therapy. Adv Drug Deliv Rev. 2015;85:57–64.
   PubMed Web of Science ®Google Scholar
• Dalhoff A. Pharmacokinetics and pharmacodynamics of aerosolized antibacterial agents in chronically infected cystic fibrosis patients. Clin Microbiol Rev. 2014;27(4):753–782.
   PubMed Web of Science ®Google Scholar
• Martinez MN, Papich MG, Drusano GL. Dosing regimen matters: the importance of early intervention and rapid attainment of the pharmacokinetic/pharmacodynamic target. Antimicrob Agents Chemother. 2012;56(6):2795–2805.
   PubMed Web of Science ®Google Scholar
• Dhanani JA, Diab S, Chaudhary J, et al. Lung pharmacokinetics of tobramycin by intravenous and nebulized dosing in a mechanically ventilated healthy ovine model. Anesthesiology. 2019;131(2):344–355.
   PubMed Web of Science ®Google Scholar
• Morais CLM, Nascimento JWL, Ribeiro AC, et al. Nebulization of vancomycin provides higher lung tissue concentrations than intravenous administration in ventilated female piglets with healthy lungs. Anesthesiology. 2020;132(6):1516–1527.
   PubMed Web of Science ®Google Scholar
• Boisson M, Mimoz O, Hadzic M, et al. Pharmacokinetics of intravenous and nebulized gentamicin in critically ill patients. J Antimicrob Chemother. 2018;73(10):2830–2837.
   PubMed Web of Science ®Google Scholar
• Westerman EM, De Boer AH, Le Brun PP, et al. Dry powder inhalation of colistin in cystic fibrosis patients: a single dose pilot study. J Cyst Fibros. 2007;6(4):284–292.
   PubMed Web of Science ®Google Scholar
• Cazzola M, Matera MG, Noschese P. Parenteral antibiotic therapy in the treatment of lower respiratory tract infections. Strategies to minimize the development of antibiotic resistance. Pulm Pharmacol Ther. 2000;13(6):249–256.
   PubMed Web of Science ®Google Scholar
• Sou T, Kukavica-Ibrulj I, Soukarieh F, et al. Model-based drug development in pulmonary delivery: pharmacokinetic analysis of novel drug candidates for treatment of Pseudomonas aeruginosa lung infection. J Pharm Sci. 108(1): 630–640. 2019.
   PubMed Web of Science ®Google Scholar
• Bos AC, van Holsbeke C, de Backer JW, et al. Patient-specific modeling of regional antibiotic concentration levels in airways of patients with cystic fibrosis: are we dosing high enough? PLoS One. 2015;10(3):e0118454.
   PubMed Web of Science ®Google Scholar
• Weers J. Comparison of phospholipid-based particles for sustained release of ciprofloxacin following pulmonary administration to bronchiectasis patients. Pulm Ther. 2019;5(2):127–150.
   PubMedGoogle Scholar
• Raut A, Dhapare S, Venitz J, et al. Pharmacokinetic profile analyses for inhaled drugs in humans using the lung delivery and disposition model. Biopharm Drug Dispos. 2020;41(1–2):32–43.
   PubMed Web of Science ®Google Scholar
• Eissing T, Kuepfer L, Becker C, et al. A computational systems biology software platform for multiscale modeling and simulation: integrating whole-body physiology, disease biology, and molecular reaction networks. Front Physiol. 2011;2:4.
   PubMed Web of Science ®Google Scholar
• Boger E, Fridén M. Physiologically based pharmacokinetic/pharmacodynamic modeling accurately predicts the better bronchodilatory effect of inhaled versus oral salbutamol dosage forms. J Aerosol Med Pulm Drug Deliv. 2019;32(1):1–12.
   PubMed Web of Science ®Google Scholar
• Artzy-Schnirman A, Hobi N, Schneider-Daum N, et al. Advanced in vitro lung-on-chip platforms for inhalation assays: from prospect to pipeline. Eur J Pharm Biopharm. 2019;144:11–17.
   PubMed Web of Science ®Google Scholar
• Organisation for Economic Co-operation and Development. Guidance document on good in vitro method practices (GIVIMP). 2018. Available from: https://www.oecd.org/env/guidance-document-on-good-in-vitro-method-practices-givimp-9789264304796-en.htm
   Google Scholar