Phase II dose-ranging trial of the early bactericidal activity of PA-824

Abstract

PA-824 is a novel nitroimidazo-oxazine under evaluation as an antituberculosis agent. A dose-ranging randomized study was conducted to evaluate the safety, tolerability, pharmacokinetics, and early bactericidal activity of PA-824 in drug-sensitive, sputum smear-positive adult pulmonary-tuberculosis patients to find the lowest dose giving optimal bactericidal activity (EBA). Fifteen patients per cohort received oral PA-824 in doses of 50 mg, 100 mg, 150 mg, or 200 mg per kg body weight per day for 14 days. Eight subjects received once-daily standard antituberculosis treatment with isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) as a positive control. The primary efficacy endpoint was the mean rate of decline in log CFU of Mycobacterium tuberculosis in sputum incubated on agar plates from serial overnight sputum collections, expressed as log(10) CFU/day/ml sputum (± standard deviation). The mean 14-day EBA of HRZE was consistent with previous studies (0.177 ± 0.042), and that of PA-824 at 50 mg, 100 mg, 150 mg, and 200 mg was 0.063 ± 0.058, 0.091 ± 0.073, 0.078 ± 0.074, and 0.112 ± 0.070, respectively. Although the study was not powered for testing the difference between arms, there was a trend toward significance, indicating a lower EBA at the 50-mg dose. Serum PA-824 levels were approximately dose proportional with respect to the area under the time-concentration curve. All doses were safe and well tolerated with no dose-limiting adverse events or clinically significant QTc changes. A dose of 100 mg to 200 mg PA-824 daily appears to be safe and efficacious and will be further evaluated as a component of novel antituberculosis regimens for drug-sensitive and drug-resistant tuberculosis.

Fig 1

Patient disposition. In the 50-mg group, 1 patient was withdrawn due to spontaneous pneumothorax requiring tube thoracostomy, which was judged by the investigator not to be drug related. In the 50-mg and 100-mg PA-824 and the HRZE groups, one patient each was lost to follow-up between the 1-month and the 6-month follow-up visits.

Fig 2

Bilinear regression of log₁₀ CFU (A) and TTP (B) on the day of treatment. Shown is bilinear regression with an inflection point of 2.5 days, illustrating the early bactericidal activity of PA-824 measured by the decline in CFU of M. tuberculosis (A) and by the increase in time to positivity (B) in liquid culture following treatment with PA-824 doses of 50 mg, 100 mg, 150 mg, and 200 mg and Rifafour e275 (HRZE).

Fig 3

PA-824 plasma concentrations. Shown are arithmetic mean PA-824 plasma concentrations determined intensively over the first and the last 24 h of treatment and predose from day 2 to day 13 in patients receiving doses of 50 mg, 100 mg, 150 mg, and 200 mg. The shapes of the concentration-time profiles were similar with increasing doses, indicating that neither the absorption nor the elimination kinetics appear to change with the dose for all PA-824 groups.