Randomized dose-ranging study of the 14-day early bactericidal activity of bedaquiline (TMC207) in patients with sputum microscopy smear-positive pulmonary tuberculosis

Abstract

Bedaquiline is a new antituberculosis agent targeting ATP synthase. This randomized, double-blinded study enrolling 68 sputum smear-positive pulmonary tuberculosis patients evaluated the 14-day early bactericidal activity of daily doses of 100 mg, 200 mg, 300 mg, and 400 mg bedaquiline, preceded by loading doses of 200 mg, 400 mg, 500 mg, and 700 mg, respectively, on the first treatment day and 100 mg, 300 mg, 400 mg, and 500 mg on the second treatment day. All groups showed activity with a mean (standard deviation) daily fall in log10 CFU over 14 days of 0.040 (0.068), 0.056 (0.051), 0.077 (0.064), and 0.104 (0.077) in the 100-mg, 200-mg, 300-mg, and 400-mg groups, respectively. The linear trend for dose was significant (P = 0.001), and activity in the 400-mg dose group was greater than that in the 100-mg group (P = 0.014). All of the bedaquiline groups showed significant bactericidal activity that was continued to the end of the 14-day evaluation period. The finding of a linear trend for dose suggests that the highest dose compatible with safety considerations should be taken forward to longer-term clinical studies.

Fig 1

Disposition of patients. *, one patient randomized to 300 mg BDQ was withdrawn before drug treatment was initiated and one patient following two doses of 400 mg BDQ, both for laboratory abnormalities at baseline that only became available after randomization. One patient in the 300 mg group was withdrawn in error.

Fig 2

Early bactericidal activity of BDQ administered in doses of 100 mg, 200 mg, 300 mg, and 400 mg on treatment days 3 to 14, preceded by single daily loading doses of 200 mg, 400 mg, 500 mg, and 700 mg, respectively, on treatment day 1 and 100 mg, 300 mg, 400 mg, and 500 mg, respectively, on treatment day 2. Rifafour (isoniazid, rifampin, pyrazinamide, and ethambutol) was used as a positive control. Early bactericidal activity was measured as the daily fall in CFU of M. tuberculosis and the daily prolongation of time to positive signal (TTP) in hours. The slopes are modeled using bilinear regression with slope changes at 2.5 days for Rifafour, at 3.5 days for BDQ measured with CFU, and at 7.5 days for BDQ measured with TTP.

Fig 3

Geometric mean plasma concentrations of BDQ following administration of BDQ in doses of 100 mg, 200 mg, 300 mg, and 400 mg on treatment days 3 to 14, preceded by single daily loading doses of 200 mg, 400 mg, 500 mg, and 700 mg, respectively, on treatment day 1 and 100 mg, 300 mg, 400 mg, and 500 mg, respectively, on treatment day 2. Full pharmacokinetic profiles are provided for doses administered on days 1 (0 to 24 h), 8 (168 to 192 h), and 14 (312 to 336 h), with trough plasma concentrations provided for the other days.

Fig 4

Relationship of the early bactericidal activity (EBA) of BDQ to the area under the concentration-time curve (AUC) of BDQ for the different dosage groups. BDQ was administered in doses of 100 mg, 200 mg, 300 mg, and 400 mg on days 3 to 14, preceded by single daily loading doses of 200 mg, 400 mg, 500 mg, and 700 mg, respectively, on treatment day 1 and 100 mg, 300 mg, 400 mg, and 500 mg, respectively, on treatment day 2. EBA over treatment days 0 to 2 and 0 to 14 was measured by the daily fall in CFU of M. tuberculosis (A) or the daily prolongation of time (hours) to positive signal (TTP) (B) and plotted against AUC on treatment days 1 and 14, respectively. EBA and AUC are means. Error bars indicate standard errors.