The renewed interest in inhalation delivery over recent years has led to an expansion in the understanding of lung pharmacokinetics.
Historically optimisation of inhaled drugs focused largely on development of material properties, consistent with achieving a good
lung deposition, alongside demonstrating appropriate in vivo efficacy with little understanding of the relationship to pharmacokinetics in
the lung. Recent efforts have led to an increased understanding of lung concentrations and how to maximise exposure in order to achieve
the desired pharmacological response at a dose consistent with development of an inhaled product. Although there is a prerequisite for
excellent potency in inhalation delivery, it is essential that this be combined with pharmacokinetic properties that allow sufficient free
concentration at the effect site in lung to exert the pharmacological response for an appropriate dosing interval. Increases in basicity, polarity
and/or decreases in aqueous solubility can extend pharmacokinetic duration and assist in finding the right balance between lung and
systemic exposure. Current evidence suggests there are similarities in lung retention in rat and dog and that animal lung concentration
data can enable pharmacokinetic-pharmacodynamic relationships to be derived thus providing more confidence in the requirements for
man. Although inhaled delivery is challenging from a pharmacokinetic point of view, direct evaluation of exposure in the target organ has
enabled further understanding of the drivers for drug disposition and highlighted the need for further development of predictive lung
pharmacokinetic tools in the future.
Keywords: Affinity, exposure, inhalation, lung pharmacokinetics, solubility, unbound fraction
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