Pharmacokinetics of Orally Inhaled Drug Products

Abstract

The presentations at the Orlando Inhalation Conference on pharmacokinetic (PK) studies indicated that PK is the most sensitive methodology for detecting formulation differences of oral inhaled drug products (OIDPs) that have negligible gastrointestinal bioavailability or for which oral absorption can be prevented (e.g., ingestion of charcoal). PK studies, therefore, may represent the most appropriate methodology for assessing local and systemic bioequivalence (BE). It was believed by many (but not all participants) that potential differences between formulations are more likely to be detected in healthy adult volunteers, as variability is reduced while deposition to peripheral areas is not restricted. A study design allowing assessment and statistical consideration of intra-subject and inter-batch variability within the evaluation of BE studies was suggested, while optimal inhalation technique during PK studies should be enforced to decrease variability. Depending on the drug and in vitro method, in vitro tests may not detect differences in PK parameters. Harmonization of BE testing requirements among different countries should be encouraged to improve global availability of low cost OIDPs and decrease industry burden.

Fig. 1

Scheme describing the fate of inhalation drugs

Fig. 2

Effect of dissolution rate, geography of deposition, and mucociliary clearance on systemic exposure (assuming negligible oral bioavailability). Cl _muc mucociliary clearance, k _a absorption rate constant, CL systemic clearance

Fig. 3

Comparison of pharmacokinetics, pharmacodynamics studies, and scintigraphy for BE decisions