Pharmacodynamic biomarkers for quantifying the mycobacterial effect of high doses of rifampin in patients with rifampin-susceptible pulmonary tuberculosis

Abstract

Background: Suboptimal drug exposure in patients with drug-susceptible tuberculosis (DS-TB) can drive treatment failure. Pharmacodynamics (PD) biomarkers such as the plasma TB drug-activity (TDA) assay may guide dose finding studies and predict microbiological outcomes differently than conventional indices. Methods: A study was nested from phase 2b randomized double-blind controlled trial of Tanzanian patients who received a 600 mg, 900 mg, or 1200 mg with a standard dose for DS-TB. Serum at 6 weeks collected over 24-h at 2-h intervals was collected for rifampin area under the concentration-time curve relative to minimum inhibitory concentration (AUC 0-24 /MIC) or peak concentration and MIC (C max /MIC). TDA was the ratio of time-to-positive growth of the patient's Mycobacterium tuberculosis isolates with and without coculture of patient's plasma collected at C max. Spearman's rank correlation (r) between PD parameters and culture convention on both liquid and solid culture media. Results: Among 10 patients, 600 mg (3), 900 mg (3), and 1200 mg (4) of rifampin dosages. The mean ± standard deviation (SD) of AUC 0-24 /MIC for patients on 600 mg was 168 ± 159 mg·h/L, on 900 mg was 169 ± 166 mg·h/L, and on 1200 mg was 308 ± 238 mg·h/L. The mean-TDA (SD) was 2.56 (±0.75), 1.5 (±0.59), and 2.29 (±1.08) for patients on 600 mg, 900 mg, and 1200 mg rifampin doses, respectively. Higher TDA values correlated with faster time to culture convention on both liquid (r = -0.55, P = 0.099) and solid media (r = -0.65, P = 0.04). Conclusions: TDA and rifampin AUC 0-24 /MIC did not trend as expected with rifampin dose, but TDA better predicted the time to sputum culture conversion. TDA may provide additional discrimination in predicting treatment response for some regimens distinct from plasma exposure relative to MIC or mg/kg dose.