No abstract

g 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. PA-824 is a new chemical entity and a member of a class of compounds known as nitroimidazo-oxazines, with significant antituberculosis activity and a unique mechanism of action (11). Preclinical and clinical studies suggest that PA-824 may assist in shortening tuberculosis (TB) treatment regimens and contribute to the management of drug-resistant TB (2, 9, 10). An earlier dose-ranging study of the early bactericidal activity (EBA) of PA-824 was conducted over 14 days in sputum smear-positive pulmonary-TB patients using PA-824 doses of 200 mg, 600 mg, 1,000 mg, and 1,200 mg/kg body weight. The data showed PA-824 to be well tolerated over the dose range evaluated, but despite increasing exposure with increasing doses, the resulting EBAs were equivalent for all four doses tested, with a mean daily fall in CFU of Mycobacterium tuberculosis of 0.098 log 10 CFU/day/ml sputum (2). In view of the lack of EBA dose response, lower doses of 50 mg, 100 mg, 150 mg, and 200 mg PA-824 were selected for further study. Evaluation of the EBA of PA-824 at these lower doses over 14 days, accompanied by evaluation of pharmacokinetics (PK) and safety endpoints, was expected to identify both a minimally efficacious dose and the lowest dose safely inducing maximal bactericidal efficacy to inform the choice of dose for later-stage clinical devel...

SQ109 alone or with rifampicin was safe over 14 days. Upon co-administration with rifampicin, 300 mg of SQ109 yielded a higher exposure than the 150 mg dose. SQ109 did not appear to be active alone or to enhance the activity of rifampicin during the 14 days of treatment.

AZD5847 is an oxazolidinone antibiotic with in vitro activity against Mycobacterium tuberculosis. The objective of this study was to evaluate the antimycobacterial activity, safety, and pharmacokinetics of AZD5847 in patients with pulmonary tuberculosis. Groups of 15 treatment-naive, sputum smear-positive adults with pulmonary tuberculosis were randomly assigned to receive AZD5847 at one of four doses (500 mg once daily, 500 mg twice daily, 1,200 mg once daily, and 800 mg twice daily) or daily standard chemotherapy. The primary efficacy endpoint was the mean daily rate of change in the log 10 number of CFU of M. tuberculosis per milliliter of sputum, expressed as the change in log 10 number of CFU per milliliter of sputum per day. The mean 14-day activity of the combination of isoniazid, rifampin, ethambutol, and pyrazinamide (؊0.163 log 10 CFU/ml sputum/day; 95% confidence interval [CI], ؊0.193, ؊0.133 log 10 CFU/ml sputum/day) was consistent with that found in previous studies. AZD5847 at 500 mg twice daily significantly decreased the number of CFU on solid medium (؊0.039; 95% CI, ؊0.069, ؊0.009; P ‫؍‬ 0.0048).