Estimation of Fraction Dissolved After Intratracheal Delivery of a Potent Janus Kinase Inhibitor, iJAK-001, with Low Solubility in Rat and Sheep: Impact of Preclinical PKPD on Inhaled Human Dose Projection

J Aerosol Med Pulm Drug Deliv. 2019 Oct;32(5):251-265. doi: 10.1089/jamp.2018.1492. Epub 2019 May 14.

Abstract

Background: A highly potent pan-Janus kinase (JAK) inhibitor with excellent kinome selectivity was developed for topical delivery to treat severe asthma. This poorly soluble drug discovery candidate, iJAK-001, is expected to exhibit long duration of JAK/STAT pathway inhibition at low doses in asthmatics because of depot effect after dry powder inhalation. Human dose projection for inhaled molecules with low aqueous solubility remains to be a daunting challenge because of several limitations: (1) bioanalytical measurement of dissolved fraction after inhalation of solid particles is uncertain; (2) distribution of these particles is not homogenous in the lung; (3) in vitro solubility measurements to estimate fraction dissolved may not be a reflection of local surface lung concentration; (4) lack of a surrogate biomarker of lung target engagement, and (5) invasive procedure needed to sample human lung tissue in the clinic. Methods: We leveraged in silico, in vitro, and in vivo tools preclinically and found significant differences in lung to plasma partition ratio when iJAK-001 was given intravenously (IV) or intratracheally in a solution-based formulation versus that in suspension, as well as pharmacodynamic response in preclinical asthma models when delivered systemically via IV infusion versus inhaled. Results and Conclusion: The combined results from above suggest that caution must be exercised using either lung or plasma exposure for human dose projection. Instead, using the local inhibitor concentration estimate based on delivery efficiency, dose, fraction absorbed, and rate of absorption normalized by lung (cardiac) blood flow may be more appropriate for dose projection.

Keywords: JAK inhibitor; asthma; eosinophil; fraction absorbed; preclinical PKPD; tofacitinib; topical inhalation delivery.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Inhalation
  • Animals
  • Asthma / drug therapy*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Dry Powder Inhalers
  • Humans
  • Janus Kinase Inhibitors / administration & dosage*
  • Janus Kinase Inhibitors / pharmacokinetics
  • Janus Kinase Inhibitors / pharmacology
  • Lung / metabolism*
  • Male
  • Rats
  • Rats, Inbred BN
  • Rats, Wistar
  • Sheep
  • Solubility
  • Tissue Distribution

Substances

  • Janus Kinase Inhibitors