Pharmacokinetic Modeling of Systemic Uptake Following Pulmonary Delivery of a Macromolecular Drug in a Sustained Release Formulation

Abstract

ABSTRACT

A pharmacokinetic model was developed to analyze systemic drug levels observed after a controlled release formulation of a macromolecular drug was administered via the lung. In addition to the consideration of classical pharmacokinetic parameters, our four-compartment model addresses issues such as the clearance of intact formulation particles from the lung and the drug's release rate from the formulation into the lung lumen. Using a system-analysis approach, the effect that each of those may have on the resulting plasma drug profiles was assessed, in particular with reference to the potential to generate sustained plasma drug levels. Our analysis indicated that the specifics of the drug's release from the formulation affected those profiles only marginally, while the formulation's residence time in the respiratory tract played a key role in determining the temporal dependence of the plasma drug levels. The implications that these findings may have on the utilization of liposomal formulations for controlled pulmonary delivery of macromolecular drugs were discussed.

The model presented was used to analyze the plasma levels observed after a liposomal formulation of a polypeptide drug was administered directly to the lungs of sedated dogs.