Microparticles specific for lung delivery: in-vivo drug distribution in monkeys

Abstract

In spite of extensive research in tuberculosis (TB), it is still one of the major infectious diseases and cause of high mortality worldwide. To enhance efficacy with lower dosing, newer drug delivery systems has been developed which provide targeted drug delivery and controlled release at the primary site of infection, i.e., the lung macrophage. Our lab has previously reported poly(D, L-lactic acid) (PLA) microparticles containing rifabutin (RFB) and isoniazid (INH) for pulmonary delivery and explored various facets of treatment with microparticle DPI. We have utilized this dry powder aerosol drug delivery system to deposit drugs directly at the site of infection in lungs and have been investigating such DPI as a novel approach to increase therapeutic efficacy, patient compliance and lower toxicity. Data from murine models of DPI delivery suggests that aerosolized delivery of anti-TB drugs is more effective than conventional drug therapies in maintaining therapeutic concentration at the site of infection. Most of the previous studies were primarily concerned with acute administration of drug-containing delivery systems and evaluation of their pharmacokinetic profile in rodents. The aim of present study was to evaluate pharmacokinetics, biodistribution and toxicity parameters of RFB and INH incorporated in DPI microparticles after ninety days of repeated dosing in rhesus macaques in order to establish steady-stae pharmacokinetics and preclinical safety of the formulation prior to humans clinical trials.