Pretomanid (PA-824)

2 years -80 in solvent

Administered via p. o.

M. tuberculosis H37Rv

2.0 ug/mL - 8.0 pg/mL

PA-824 is formulated either in 0.5% methylcellulose (MC) or in cyclodextrin/lecithin (CM2).

In the rapid tuberculosis mouse model, PA-824 shows significant anti-microbial activity in a dose-dependent manner: at 50 mg/kg, PA-824 in MC produces a more than 1-log reduction of the CFU in the lungs, at 100 mg/kg it produces about a 2-log reduction, and at 300 mg/kg it produces a 3-log reduction. Furthermore, long-term treatment of PA-824 at 100 mg/kg in cyclodextrin/lecithin also leads to the reduction of the bacterial load below 500 CFU in the lungs and spleen. [1], PA-824 exhibits time-dependent anti-microbial activity in a murine model of tuberculosis with a maximal observed bactericidal effect of 0.1 log CFU/day over 24 days. [3]

A method is used to determine the MICs by a microdilution plate assay by using M. tuberculosis H37Rv. INH is dissolved in sterile, double-distilled water at a stock concentration of 500 ug/ml. PA-824 is dissolved in 100% dimethyl sulfoxide (DMSO) to a stock concentration of 100 ug/ml. A 1:2 dilution series of both compounds is made in a separate 96-well microtiter plate by using the same diluents. The interior 60 wells of a 96-well round-bottom microtiter assay plate are seeded with 98 ul of bacterial suspension. Two microliters of each drug is transferred to the assay plate wells containing bacteria. The final concentrations of INH in the wells range from 10.0 to 0.039 ug/mL, the final concentrations of PA-824 range from 2.0 ug/mL to 8.0 pg/mL. The assay plates are incubated at 37 C for at least 21 days and are observed every 3 to 4 days to evaluate changes in growth. Inhibition of growth is determined both by visual examination and with a spectrophotometer at an OD600.

PA-824 is an anti-tuberculosis drug for tuberculosis with MIC less than 2.8 μM.Phase 2.

PA-824 is an experimental anti-tuberculosis drug.