Model predictions of regional deposition in the respiratory tract are useful in assessing factors that influence the effectiveness of aerosol delivery. Regional deposition models have previously been coupled with models of mucous production and clearance to estimate initial concentrations of drug deposited in the airway surface liquid (ASL) lining tracheobronchial airways.
Methods:
Established models of regional deposition and ASL volumes were used to provide input to a new model evaluating the disposition of drug resulting from dissolution or release, absorption, and mucociliary clearance. Additional modeling of oral absorption, distribution, and elimination allowed prediction of systemic exposure. Herein, predicted ASL and plasma concentrations of free (dissolved or unencapsulated) ciprofloxacin over time are reported for a healthy, adult lung model following inhalation of single doses of nebulized liposomal (6 mL of liposomal ciprofloxacin for inhalation, 50 mg/mL, or 6 mL of Pulmaquin, 210 mg; Aradigm) and dry powder (32.5 and 65 mg doses; Bayer) formulations.
Results:
Over a range of mucous production rates and tracheal clearance velocities, peak ASL concentrations of free ciprofloxacin were consistently greater for Pulmaquin than for other formulations investigated, owing to the presence of free drug in the nebulized Pulmaquin formulation. The time that ASL concentrations of free drug remained above the minimum inhibitory concentration for Pseudomonas aeruginosa was similar for all four formulations. Predicted plasma ciprofloxacin concentration profiles were in good agreement with available data from Phase I trials in healthy volunteers.
Conclusions:
Predictions of ASL drug concentrations over time are valuable in elucidating the roles of deposition, drug release or dissolution, and disposition on the effectiveness of inhaled aerosol therapies. For inhaled ciprofloxacin, the present results predict similar ASL concentrations of free drug over time following single doses of inhaled liposomal and dry powder formulations. The impact of multiple doses and airway disease warrants further consideration.
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