(photo: http://www.musc.edu/chp/papem)
The route of drug delivery for TB drugs is an interesting one with the usual (and valuable) room for debate about different methods. While the standard mode of delivery for most drugs is oral, there is ongoing discussion as to whether aerosol delivery of TB drugs may be a more suitable route of delivery for treating pulmonary TB.
In a recent study by Garcia-Conreras et al., dry powder aerosol delivery of PA-824 was compared to oral delivery in the guinea pig model of TB. PA-824 is an investigational TB drug currently in Phase II clinical trials. Previous studies have reported solubility issues regarding PA-824, and additional inactive substances are needed in the formulation to ensure oral delivery at therapeutic doses. M. tb infected guinea pigs were treated daily for 4 weeks with either low or high dose inhalation of dry powder aerosol PA-824 (estimated at 4.8 mg/kg or 9.7 mg.kg respectively), 40 mg/kg oral PA-824, or placebo. Untreated TB infected guinea pigs were also evaluated as controls.
Results showed that both low and high dose aerosol PA-824 inhalation displayed peak plasma concentration within 3-4 hrs and drug still present in the circulation 24hrs after initial exposure. Additionally, some inhaled PA-824 was identified in the systemic circulation. Wet tissue weight, an indirect marker of inflammation, revealed similar levels of lung or spleen inflammation for PA-824 aerosol and oral delivery which were collectively less than placebo or untreated controls.
Bacterial load in the lungs and spleen however was only significantly reduced with oral PA-824 suggesting that oral delivery may be the best route of administration for this drug. Histopathological investigation of the lungs and spleen demonstrated subtle differences between low and high dose aerosol compared to oral, although the authors highlight fewer white pulp with granulomas in high dose aerosol verses oral administration.
Overall these finding may warrant further evaluation of aerosol delivery of TB drugs considering the extended residence time and bioavailability of aerosol delivered PA-824. Furthermore, the results observed from spleen histopathology may signal an advantage aerosol delivery has over oral delivery as it relates to the pathophysiology of M. tb infection considering the aerosol drug concentration was 4-10 times less concentrated than the oral dose.
Should aerosol and nano-delivery of TB drugs be further investigated or is oral delivery sufficient? Would aerosol delivery of some drugs and not others impact treatment compliance positively or negatively? Do the histopathological results from this study suggest that drug delivery routes affect M. tb infectivity? What are your thoughts or outstanding questions? Comments? Please share them below.
Aerosol delivery in order to target the lungs for treating a disease of the lungs, seems like an avenue worth pursuing. The results of this study however have revealed a more complex pharmacolgy that expected. PA-824 is effective when delivered orally to animals and humans and may be able to localize to the TB-laden micro-environment via the bloodstream more easily than by penetrating via the broncioles. This is not to say that another class of drugs might not be best delivered by aerosol.
However, delivering one drug out of a multi-drug regimen by aerosol while the rest are delivered orally would not be ideal. Both compliance and cost of goods (including the delivery device) would be negatively impacted. These could be outweighed by a need to decrease systemic exposure due to adverse events, but PA-824 has so far proven to be comparably safe in clinical trials.
Aerosol delivery remains an intriguing route of administration for TB treatments and may be better suited for other classes of drugs.