Early Bactericidal Activity and Pharmacokinetics of PA-824 in Smear-Positive Tuberculosis Patients

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.Over four decades ago, the introduction of rifampin catalyzed a series of clinical trials leading to current recommendations for tuberculosis (TB) treatment, with the combination of isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA), supported by ethambutol (EMB) or streptomycin (SM) (17, 27). However, this regimen must be taken consistently for 6 months, preferably under supervision, to ensure sterilization of tuberculosis lesions and to prevent development of drug resistance. This relatively long treatment duration, coupled with increasing financial and administrative difficulties experienced by health care systems and the burgeoning HIV/AIDS epidemic, threatens the success of tuberculosis control programs worldwide, particularly in high-incidence areas such as sub-Saharan Africa and parts of Asia. Treatment default is all too frequent (14), and the situation is further exacerbated by the increasing proportion of new cases of tuberculosis resistant to one or more first-line agents (7, 28). New drugs are urgently needed to meet these challenges. They are needed to assist in the management of drug resistance, but also, at least as importantly, to assist in shortening treatment regimens to make tuberculosis treatment easier to supervise and reduce the therapeutic burden that tuberculosis management places on both patients and health services. In addition, current regimens cause difficulties for tuberculosis patients coinfected with HIV due to the deleterious interaction of existing first-line antituberculosis drugs and antiretroviral agents.PA-824 is a small nitroimidazo-oxazine molecule that has shown potential both in vitro and in vivo of being able to assist both in shortening the treatment regimen for tuberculosis and contributing to the treatment of drug-resistant tuberculosis patients (19, 20). Studies using anaerobic culture models have also found activity against nonreplicating Mycobacterium tuberculosis (10, 16, 24, 25). In vitro studies found the MIC of PA-824 (≤0.015 to 0.25 μg/ml) to be comparable to that of INH (0.03 to 0.06 μg/ml) (16). Studies in healthy volunteers indicated that PA-824 was well tolerated and bioavailable after oral doses without significant drug-related side effects, changes in vital signs, or abnormal laboratory values (8, 9). PA-824 has been shown to cause isolated and reversible increases in serum creatinine levels, which appear to be due to inhibition of creatinine secretion and are considered clinically benign (8, 9). The dosage levels of 200 mg, 600 mg, 1,000 mg, and 1,200 mg used in this study were selected on the basis of preclinical toxicology and efficacy data and clinical pharmacokinetic properties of PA-824 observed in healthy adult volunteers and were chosen to assist identification of the lowest efficacious dosage and the highest dosage safely inducing maximal bactericidal efficacy.Early bactericidal activity (EBA) refers to an agent''s ability to kill mycobacteria originating within pulmonary cavities during the first weeks of treatment. Determination of EBA in sputum smear-positive pulmonary tuberculosis patients by quantification of viable CFU of M. tuberculosis in an overnight sputum collection allows the comparison of different drugs with one another with regard to clinical bactericidal activity and early assessment of safety in a small number of intensively studied patients. The evaluation of a dosage-related response can guide the selection of a dosage to take forward to later clinical studies (5, 6, 12, 13). Initial studies using this technique were conducted over the first two days of treatment, as it was during this period that the most significant differences between agents were seen (12). Further experience has shown that significant advantages may accrue from extending the study period; for example, the important sterilizing agent PZA showed bactericidal activity only after four days of treatment (12), as did the novel diarylquinoline currently in development, TMC207 (4, 23).It has also been suggested that activity during the period of 2 to 14 days after treatment is started might represent the sterilizing capacity of an agent (13). Recently, evidence has been presented that the time to positivity (TTP) of M. tuberculosis in automated liquid culture systems reflects the metabolic activity of inoculated viable M. tuberculosis in sputum. TTP might represent an alternative method to colony counting for estimating the activity of viable M. tuberculosis in sputum, which might be valuable for exploring the bactericidal activities of new antituberculosis agents (22).This paper reports a proof-of-concept study that evaluated the bactericidal activity of PA-824 given as monotherapy over a range of dosages during the first 14 days of treatment of treatment-naïve patients with smear-positive pulmonary tuberculosis. Safety, tolerability, and pharmacokinetics (PK) were also evaluated.