Aerosol Pirfenidone Pharmacokinetics after Inhaled Delivery in Sheep: a Viable Approach to Treating Idiopathic Pulmonary Fibrosis

Kaminskas, Lisa M.; Landersdorfer, Cornelia B.; Bischof, Robert; Leong, Nathania; Ibrahim, Jibriil; Davies, Ann D. M.; Pham, Scott; Beck, Steven; Montgomery, A. Bruce; Surber, Mark W.

doi:10.1007/s11095-019-2732-2

Cited by 23 publications

(15 citation statements)

References 24 publications

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“…Both drugs were reformulated as a solution for inhaled administration, which holds promise to reduce systemic side-effects, maximise local efficacy and possibly enable dose escalation for additional efficacy in IPF patients [90,91]. Inhaled pirfenidone and nintedanib proved to have good pharmacokinetics, delivering an oral-equivalent lung maximum concentration with lower systemic levels, and to be well-tolerated and effective in several animal models [90][91][92]. These promising observations have to be confirmed in human trials.…”

Section: Inhaled Antifibroticsmentioning

confidence: 99%

Antifibrotic drugs in lung transplantation and chronic lung allograft dysfunction: a review

Bos¹,

Sadeleer

Vanstapel

et al. 2021

Eur Respir Rev

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This review aims to provide an overview of pre-transplant antifibrotic therapy on peri-transplant outcomes and to address the possible role of antifibrotics in lung transplant recipients with chronic lung allograft dysfunction.Lung transplantation is an established treatment modality for patients with various end-stage lung diseases, of which idiopathic pulmonary fibrosis and other progressive fibrosing interstitial lung diseases are growing indications. Theoretically, widespread use of antifibrotics prior to lung transplantation may increase the risk of bronchial anastomotic complications and impaired wound healing.Long-term graft and patient survival are still hampered by development of chronic lung allograft dysfunction, on which antifibrotics may have a beneficial impact.Antifibrotics until the moment of lung transplantation proved to be safe, without increasing peri-transplant complications. Currently, best practice is to continue antifibrotics until time of transplantation. In a large multicentre randomised trial, pirfenidone did not appear to have a beneficial effect on lung function decline in established bronchiolitis obliterans syndrome. The results of antifibrotic therapy in restrictive allograft syndrome are eagerly awaited, but nonrandomised data from small case reports/series are promising.

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Section: Inhaled Antifibroticsmentioning

confidence: 99%

Antifibrotic drugs in lung transplantation and chronic lung allograft dysfunction: a review

Bos¹,

Sadeleer

Vanstapel

et al. 2021

Eur Respir Rev

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“…Such a dosage form can be an inhaled liposomal form of pirfenidone, including one based on dipalmitoylphosphatidylcholine (DPPC), a major phospholipid of human lung surfactant [8]. Inhaled forms of PF prevent the development of phototoxicity [9,10].…”

Section: Introductionmentioning

confidence: 99%

Cholesterol Significantly Affects the Interactions between Pirfenidone and DPPC Liposomes: Spectroscopic Studies

et al. 2022

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In this work, we studied the effect of as on the interaction of membrane DPPC with the key antifibrotic drug pirfenidone. Liposomal forms of pirfenidone were obtained using passive loading. The addition of cholesterol reduces the loading efficiency of pirfenidone by 10%. The main binding site of pirfenidone in DPPC liposomes is the carbonyl group: the interaction with PF significantly increases the proportion of low-hydrated carbonyl groups as revealed by ATR-FTIR spectroscopy. The phosphate group acts as an additional binding site; however, due to shielding by the choline group, this interaction is weak. The hydrophobic part of the bilayer is not involved in PF binding at room temperature. Cholesterol changes the way of interaction between carbonyl groups and pirfenidone probably because of the formation of two subpopulations of DPPC and causes a dramatic redistribution of carbonyl groups onto the degrees of hydration. The proportion of moderately hydrated carbonyl groups increases, apparently due to the deepening of pirfenidone into the circumpolar region of the bilayer. For the first time, a change in the microenvironment of pirfenidone upon binding to liposomes was shown: aromatic moiety interacts with the bilayer.

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“…The preparation, and surgical cannulation, of sheep under isoflurane anesthesia were conducted as described previously with some modification to antibiotics and analgesics used (details of pre- and post-surgical infection control and pain relief are reported in the supplementary information) ( Enkhbaatar et al, 2003 ; Ryan et al, 2016 ; Kaminskas et al, 2020 ). Briefly, the right jugular vein was initially cannulated in all sheep to allow for saline (0.9% NaCl) administration during and after surgery (during the recovery phase—24–48 h post surgery), intravenous (IV) dosing and serial blood sample collection over the experimental phase (0–5 days post liposome administration).…”

Section: Methodsmentioning

confidence: 99%

Liposomes are Poorly Absorbed via Lung Lymph After Inhaled Administration in Sheep

et al. 2022

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Enhancing the delivery of therapeutic agents to the lung lymph, including drugs, transfection agents, vaccine antigens and vectors, has the potential to significantly improve the treatment and prevention of a range of lung-related illnesses. One way in which lymphatic delivery can be optimized is via the use of nanomaterial-based carriers, such as liposomes. After inhaled delivery however, there is conflicting information in the literature regarding whether nanomaterials can sufficiently access the lung lymphatics to have a therapeutic benefit, in large part due to a lack of reliable quantitative pharmacokinetic data. The aim of this work was to quantitatively evaluate the pulmonary lymphatic pharmacokinetics of a model nanomaterial-based drug delivery system (HSPC liposomes) in caudal mediastinal lymph duct cannulated sheep after nebulized administration to the lungs. Liposomes were labelled with 3H-phosphatidylcholine to facilitate evaluation of pharmacokinetics and biodistribution in biological samples. While nanomaterials administered to the lungs may access the lymphatics via direct absorption from the airways or after initial uptake by alveolar macrophages, only 0.3 and 0.001% of the 3H-lipid dose was recovered in lung lymph fluid and lymph cell pellets (containing immune cells) respectively over 5 days. This suggests limited lymphatic access of liposomes, despite apparent pulmonary bioavailability of the 3H-lipid being approximately 17%, likely a result of absorption of liberated 3H-lipid after breakdown of the liposome in the presence of lung surfactant. Similarly, biodistribution of 3H in the mediastinal lymph node was insignificant after 5 days. These data suggest that liposomes, that are normally absorbed via the lymphatics after interstitial administration, do not access the lung lymphatics after inhaled administration. Alternate approaches to maximize the lung lymphatic delivery of drugs and other therapeutics need to be identified.

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Aerosol Pirfenidone Pharmacokinetics after Inhaled Delivery in Sheep: a Viable Approach to Treating Idiopathic Pulmonary Fibrosis

Cited by 23 publications

References 24 publications

Antifibrotic drugs in lung transplantation and chronic lung allograft dysfunction: a review

Antifibrotic drugs in lung transplantation and chronic lung allograft dysfunction: a review

Cholesterol Significantly Affects the Interactions between Pirfenidone and DPPC Liposomes: Spectroscopic Studies

Liposomes are Poorly Absorbed via Lung Lymph After Inhaled Administration in Sheep

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