A preclinical pharmacokinetic modeling approach to the biopharmaceutical characterization of immediate and microsphere-based sustained release pulmonary formulations of rifampicin.

A rifampicin-hydroxypropyl-beta-cyclodextrin (RIF-HPCD) complex solution and two RIF-loaded PLGA microspheres with slow or fast release rates were nebulized into the rat lungs for a comparative biopharmaceutical evaluation. A pharmacokinetic model was applied to model systemic RIF concentrations and to predict the RIF concentrations in the lung epithelial lining fluid (ELF). With intravenous RIF and nebulized RIF-HPCD, plasma profiles and predicted RIF ELF profiles were superimposed indicating that RIF diffused almost instantaneously through the broncho-alveolar barrier. 5h post administration RIF ELF predicted concentrations were in agreement with experimental concentrations determined using the broncho-alveolar lavage (BAL) sampling method. Microsphere formulations resulted in different plasma concentration profiles, demonstrating RIF sustained release. The PK model predicted the ELF concentrations to be much higher with microspheres than with nebulized and IV RIF, over a prolonged time period, which was confirmed by BAL sampling. In conclusion this work demonstrated the benefit of using sustained-release microspheres administered as aerosols to maintain, over a prolonged time period, high levels of pulmonary concentrations of drugs characterized by a rapid absorption through the broncho-alveolar barrier. Moreover, PK modeling was a useful tool to build concentration-versus-time profiles in non-readily accessible ELF compartment and to assess the biopharmaceutical properties of aerosol formulations for lung delivery.