Early bactericidal activity and pharmacokinetics of PA-824 in smear-positive tuberculosis patients

Abstract

PA-824 is a novel nitroimidazo-oxazine being evaluated for its potential to improve tuberculosis (TB) therapy. This randomized study evaluated safety, tolerability, pharmacokinetics, and extended early bactericidal activity of PA-824 in drug-sensitive, sputum smear-positive, adult pulmonary tuberculosis patients. Fifteen patients per cohort received 1 of 4 doses of oral PA-824: 200, 600, 1,000, or 1,200 mg per day for 14 days. Eight subjects received once daily standard antituberculosis treatment as positive control. The primary efficacy endpoint was the mean rate of change in log CFU of Mycobacterium tuberculosis in sputum incubated on agar plates from serial overnight sputum collections, expressed as log10 CFU/day/ml (+/-standard deviation [SD]). The drug demonstrated increases that were dose linear but less than dose proportional in serum concentrations in doses from 200 to 1,000 mg daily. Dosing of 1,200 mg gave no additional exposure compared to 1,000 mg daily. The mean daily CFU fall under standard treatment was 0.148 (+/-0.055), consistent with that found in previous studies. The mean daily fall under PA-824 was 0.098 (+/-0.072) and was equivalent for all four dosages. PA-824 appeared safe and well tolerated; the incidence of adverse events potentially related to PA-824 appeared dose related. We conclude that PA-824 demonstrated bactericidal activity over the dose range of 200 to 1,200 mg daily over 14 days. Because maximum efficacy was unexpectedly achieved at the lowest dosage tested, the activity of lower dosages should now be explored.

FIG. 1.

Patient disposition. Four participants did not complete the 14-day period of drug intake. Two patients randomized to PA-824 200 mg and one patient randomized to PA-824 1,200 mg were withdrawn due to adverse events not related to study medication (hemoptysis, n = 1; Wolff-Parkinson-White syndrome, n = 1; urinary tract infection, n = 1). One patient randomized to 1,000 mg PA-824 withdrew consent.

FIG. 2.

(A) CFU counts of all treatments over time. Shown is a fitted bilinear regression line for all PA-824 treatment groups, with 95% confidence intervals represented by dotted lines, illustrating the daily decline in CFU from baseline as mean log CFU/day. The horizontal lines are the mean baseline count (top) with lower 95% confidence interval (bottom). Single data points represent mean values of individual treatment groups. Rifafour is standard, four-drug treatment. (B) Change in CFU counts of all PA-824 treatments combined over time. Mean change from baseline in CFU is measured as log₁₀ CFU/day for all PA-824 treatment groups together with 95% confidence intervals. The horizontal line is the mean baseline count. A significant decrease is found from day 3 onwards, indicated by confidence intervals no longer including baseline.

FIG. 3.

(A) Time to culture positivity of all treatments over time. Shown is fitted bilinear regression line for all PA-824 treatment groups, with 95% confidence intervals represented by dotted lines, illustrating the daily increase in TTP from baseline as mean hours/day. The horizontal lines are the mean baseline TTP (bottom) with upper 95% confidence interval (top). Single data points represent values of individual treatment groups. Rifafour is standard, four-drug treatment. (B) Change in TTP of all PA-824 treatments combined over time. Mean change from baseline in TTP is measured as hours/day for all PA-824 treatment groups with 95% confidence intervals. The horizontal line is the mean baseline time. A significant increase is found from day 3 onwards (when the confidence intervals no longer include baseline).