An inhalable rifapentine dry powder targeting latent tuberculosis infection

John G.Y. Chan, Anneliese S. Tyne, Angel Pang, Colin Duke, Warwick J. Britton, Hak Kim Chan, Paul M. Young, and Daniela Traini

Background One third of the world population retains latent tuberculosis infection (LTBI) with a lifelong risk of developing active disease. It was recently demonstrated that two months of daily oral rifapentine in a mouse model of LTBI was as effective as the existing 9-month isoniazid regimen. Difficulties with oral dosing of rifapentine due to high plasma protein binding (97%) may be overcome by inhaled administration. Methods In vitro characterisation of an inhalable crystalline form of rifapentine included aerosol performance, particle sizing, x-ray diffractometry and resazuarin assay. Murine pharmacokinetics compared intratracheal to intraperitoneal delivery of rifapentine. Results The powder consisted of elongated crystalline particles with a mass median aerodynamic diameter of 1.68 ± 0.03 m, geometric standard deviation of 1.72 (StDev < 0.01) and a fine particle fraction of 83.2 ± 1.2%. The minimum inhibitory concentration (MIC) of the rifapentine powder was 1 ng/mL consistent with unprocessed rifapentine. Bronchoalveolar lavage (BAL) concentrations were maximal soon after administration at 0.5 hours (25 ± 6 μg/mL), declining down to 1.9 ± 1.1 μg/mL by 24 hours. Lung concentrations peaked at 321 ± 99 μg/g at 2 hours, plateauing from 12 hours onwards at 60 ± 32 μg/g. In contrast, intraperitoneal delivery only imparted 1-4 μg/g of rifapentine to lung tissue at various time-points throughout the 24 hour time period, whilst no rifapentine was detected within the BAL. Conclusions Substantial rifapentine concentrations within the pulmonary site of infection can be achieved using inhaled delivery and may realise significantly shortened LTBI treatment times.

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