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

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Abstract

Purpose

Inhaled delivery of pirfenidone to the lungs of patients with idiopathic pulmonary fibrosis holds promise to eliminate oral-observed side effects while enhancing efficacy. This study aimed to comprehensively describe the pulmonary pharmacokinetics of inhaled aerosol pirfenidone in healthy adult sheep. Methods: Pirfenidone concentrations were evaluated in plasma, lung-derived lymph and epithelial lining fluid (ELF) with data subjected to non-compartmental pharmacokinetic analysis. Results: Compartmental pharmacokinetic evaluation indicated that a 49 mg lung-deposited dose delivered an ELF Cmax of 62 ± 23 mg/L, and plasma Cmax of 3.1 ± 1.7 mg/L. Further analysis revealed that plasma pirfenidone reached Tmax faster and at higher concentrations than in lymph. These results suggested inhaled pirfenidone was cleared from the alveolar interstitium via blood faster than the drug could equilibrate between the lung interstitial fluid and lung lymphatics. However, the data also suggested that a ‘reservoir’ of pirfenidone feeds into lung lymph at later time points (after it has largely been cleared from plasma), prolonging lung lymphatic exposure.

Conclusions

This study indicates inhaled pirfenidone efficiently deposits in ELF and is cleared from the lungs by initial absorption into plasma, followed by later equilibrium with lung interstitial and lymph fluid.

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Abbreviations

AUC:

Area under the plasma concentration vs time curve

BALF:

Bronchoalveolar lavage fluid

Cmax:

Maximum concentration

ELF:

Epithelial lining fluid

Fabs:

Fraction of drug absorbed

IC50:

50% inhibitory concentration

Tmax:

Time to maximum concentration

IPF:

Idiopathic pulmonary fibrosis

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Acknowledgments and Disclosures

This study was funded by Avalyn Pharma Inc. LMK is supported by an NHMRC CDF2.

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Authors and Affiliations

  1. School of Biomedical Sciences, University of Queensland, QLD, St Lucia, 4072, Australia

    Lisa M Kaminskas

  2. Centre for Medicine Use and Safety, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia

    Cornelia B Landersdorfer

  3. Allergenix Pty Ltd, Melbourne, VIC, 3051, Australia

    Robert J Bischof, Nathania Leong, Jibriil Ibrahim & Andrew N Davies

  4. Biomedicine Discovery Institute, Monash University, Peninsula Campus, Frankston, VIC, 3199, Australia

    Andrew N Davies

  5. Avalyn Pharma Inc., 701 Pike Street, Suite 1500, Seattle, WA, 98101, USA

    Stephen Pham, Steven Beck, A. Bruce Montgomery & Mark W Surber

Authors
  1. Lisa M Kaminskas
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  2. Cornelia B Landersdorfer
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  3. Robert J Bischof
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  4. Nathania Leong
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  5. Jibriil Ibrahim
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  6. Andrew N Davies
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  7. Stephen Pham
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  8. Steven Beck
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  9. A. Bruce Montgomery
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  10. Mark W Surber
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Corresponding authors

Correspondence to Lisa M Kaminskas or Mark W Surber.

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Kaminskas, L.M., Landersdorfer, C.B., Bischof, R.J. et al. Aerosol Pirfenidone Pharmacokinetics after Inhaled Delivery in Sheep: a Viable Approach to Treating Idiopathic Pulmonary Fibrosis. Pharm Res 37, 3 (2020). https://doi.org/10.1007/s11095-019-2732-2

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  • DOI: https://doi.org/10.1007/s11095-019-2732-2

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