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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.

This review provides a vista of the current opportunities and remaining challenges in the area of in vitro-in vivo extrapolation, with particular emphasis on drug binding terms in predictive models, which has been the source of much controversy. Although the importance of fu(inc) (fraction unbound in in vitro incubations) has been acknowledged for decades, it is not always applied in practice. This is somewhat disappointing, since although it may be onerous to measure this term for large numbers of compounds, algorithms to estimate the term from logD(7.4) or logP have been detailed in the literature. These are sufficiently robust to negate routine measurement in early drug discovery. Several groups have recently established convincing relationships between unbound in vivo and in vitro metabolic intrinsic clearance (CL(int)). In the authors' laboratory, correlations of this type have been constructed for rat, dog and Man. The use and interpretation of these models within a drug discovery setting is discussed. The quantitative prediction of drug-drug interactions from in vitro cytochrome P450 (CYP) inhibition data remains a challenge. Although extensive literature databases are at last emerging, apparent ad hoc use of terms for in vivo inhibitor concentrations and only occasional consideration of fu(inc) may only have confused matters. The effect of accounting for drug binding on the accuracy of predictions is reviewed. Other themes including the impact of fu(inc) on relative activity factors (RAFs) and how in vitro data quality and inter-laboratory differences can confound quantitative human pharmacokinetic predictions are also developed.