Strategies for expediting preclinical development of drugs include using alternative (different to clinical) formulations or exposure routes to reduce compound usage. This may alter pharmacokinetics and hence efficacy and/or toxicopathology compared with the final formulation. Three p38 mitogen-activated kinase inhibitors (similar in vitro potency) with different physicochemical properties were administered to rats as dry powder or nebulised aerosols to investigate the influence of changes in particulate form on in vivo endpoints. When rats settled in restraint tubes before aerosol administration, inhaled doses calculated from lung function measurements were consistent with values derived from body weights using a published algorithm. Drug-lung deposition was 12% of the inhaled dose, correlating with the rat deposition fraction (10%) used by US-FDA officials when reviewing regulatory submissions. Drug persistence (GSK-899) in rat lung was associated with increased efficacy (inhibition of lipopolysaccharide-induced inflammation) four hours post challenge, compared with two readily absorbed drugs. However, administration of GSK-899 at a higher dose for 28 days resulted in accumulation of drug and alveolar macrophage aggregates in lungs with infiltration of neutrophils, a consequence of accumulating ‘nuisance particles’ and mild irritancy by GSK-899. GSK-361 (lipophilic; membrane permeable) resulted in lower lung exposure and efficacy, and no lung toxicopathology. Repeating experiments with compounds of different pharmacologies would confirm if these physicochemical properties support general trends for inhaled drugs or represent standalone results for these molecules. Changing aerosol form did not fundamentally change the nature of toxicopathology but presented technical limitations for evaluating the dose response. This thesis demonstrated changes in aerosol form could modulate dose response without changing the nature of toxicopathology. Membrane permeability had a more profound effect on lung clearance and toxicopathology than aqueous solubility. Given technical limitations for drugs of low aqueous solubility, the aerosol form intended for clinical formulations should be used in early preclinical studies.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:753542 |
| Date | January 2017 |
| Creators | Paul, Graham R. |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/113410/ |
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