From bench to bedside: in vitro and in vivo evaluation of a neonate-focused nebulized surfactant delivery strategy.

Autor: Bianco F; Department of Preclinical Pharmacology, R&D, Chiesi Farmaceutici S.p.A, Parma, Italy., Ricci F; Department of Preclinical Pharmacology, R&D, Chiesi Farmaceutici S.p.A, Parma, Italy., Catozzi C; Department of Preclinical Pharmacology, R&D, Chiesi Farmaceutici S.p.A, Parma, Italy., Murgia X; Scientific Consultancy, Saarbrücken, Germany., Schlun M; PARI Pharma GmbH, Starnberg, Germany., Bucholski A; PARI Pharma GmbH, Starnberg, Germany., Hetzer U; PARI Pharma GmbH, Starnberg, Germany., Bonelli S; Department of Preclinical Pharmacology, R&D, Chiesi Farmaceutici S.p.A, Parma, Italy., Lombardini M; Department of Preclinical Pharmacology, R&D, Chiesi Farmaceutici S.p.A, Parma, Italy., Pasini E; Department of Preclinical Pharmacology, R&D, Chiesi Farmaceutici S.p.A, Parma, Italy., Nutini M; Department of Preclinical Pharmacology, R&D, Chiesi Farmaceutici S.p.A, Parma, Italy., Pertile M; Department of Preclinical Pharmacology, R&D, Chiesi Farmaceutici S.p.A, Parma, Italy., Minocchieri S; Division of Neonatology, Cantonal Hospital Winterthur, Winterthur, Switzerland., Simonato M; Pediatric Research Institute 'Città della Speranza', Padova, Italy., Rosa B; Department of Preclinical Pharmacology, R&D, Chiesi Farmaceutici S.p.A, Parma, Italy., Pieraccini G; Mass Spectrometry Center (CISM), Polo Biomedico, Careggi University Hospital of Florence, Florence, Italy., Moneti G; Mass Spectrometry Center (CISM), Polo Biomedico, Careggi University Hospital of Florence, Florence, Italy., Lorenzini L; Health Science and Technologies Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Bologna, Italy., Catinella S; Department of Preclinical Pharmacology, R&D, Chiesi Farmaceutici S.p.A, Parma, Italy., Villetti G; Department of Preclinical Pharmacology, R&D, Chiesi Farmaceutici S.p.A, Parma, Italy., Civelli M; Department of Preclinical Pharmacology, R&D, Chiesi Farmaceutici S.p.A, Parma, Italy., Pioselli B; Department of Preclinical Pharmacology, R&D, Chiesi Farmaceutici S.p.A, Parma, Italy., Cogo P; Division of Pediatrics, Department of Medicine, University of Udine, Udine, Italy., Carnielli V; Polytechnic University of Marche and Azienda Ospedaliero-Universitaria Ospedali Riuniti, Ancona, Italy., Dani C; Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence School of Medicine, Careggi University Hospital of Florence, Viale Morgagni, 85, Florence, Italy. cdani@unifi.It., Salomone F; Department of Preclinical Pharmacology, R&D, Chiesi Farmaceutici S.p.A, Parma, Italy.
Jazyk: angličtina
Zdroj: Respiratory research [Respir Res] 2019 Jul 02; Vol. 20 (1), pp. 134. Date of Electronic Publication: 2019 Jul 02.
DOI: 10.1186/s12931-019-1096-9
Abstrakt: Background: Non-invasive delivery of nebulized surfactant has been a neonatology long-pursued goal. Nevertheless, the clinical efficacy of nebulized surfactant remains inconclusive, in part, due to the great technical challenges of depositing nebulized drugs in the lungs of preterm infants. The aim of this study was to investigate the feasibility of delivering nebulized surfactant (poractant alfa) in vitro and in vivo with an adapted, neonate-tailored aerosol delivery strategy.
Methods: Particle size distribution of undiluted poractant alfa aerosols generated by a customized eFlow-Neos nebulizer system was determined by laser diffraction. The theoretical nebulized surfactant lung dose was estimated in vitro in a clinical setting replica including a neonatal continuous positive airway pressure (CPAP) circuit, a cast of the upper airways of a preterm neonate, and a breath simulator programmed with the tidal breathing pattern of an infant with mild respiratory distress syndrome (RDS). A dose-response study with nebulized surfactant covering the 100-600 mg/kg nominal dose-range was conducted in RDS-modelling, lung-lavaged spontaneously-breathing rabbits managed with nasal CPAP. The effects of nebulized poractant alfa on arterial gas exchange and lung mechanics were assessed. Exogenous alveolar disaturated-phosphatidylcholine (DSPC) in the lungs was measured as a proxy of surfactant deposition efficacy.
Results: Laser diffraction studies demonstrated suitable aerosol characteristics for inhalation (mass median diameter, MMD = 3 μm). The mean surfactant lung dose determined in vitro was 13.7% ± 4.0 of the 200 mg/kg nominal dose. Nebulized surfactant delivered to spontaneously-breathing rabbits during nasal CPAP significantly improved arterial oxygenation compared to animals receiving CPAP only. Particularly, the groups of animals treated with 200 mg/kg and 400 mg/kg of nebulized poractant alfa achieved an equivalent pulmonary response in terms of oxygenation and lung mechanics as the group of animals treated with instilled surfactant (200 mg/kg).
Conclusions: The customized eFlow-Neos vibrating-membrane nebulizer system efficiently generated respirable aerosols of undiluted poractant alfa. Nebulized surfactant delivered at doses of 200 mg/kg and 400 mg/kg elicited a pulmonary response equivalent to that observed after treatment with an intratracheal surfactant bolus of 200 mg/kg. This bench-characterized nebulized surfactant delivery strategy is now under evaluation in Phase II clinical trial (EUDRACT No.:2016-004547-36).
Databáze: MEDLINE
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