Clinical significance of 2 h plasma concentrations of first-line anti-tuberculosis drugs: a prospective observational study

Objectives: To study 2 h plasma concentrations of the first-line tuberculosis drugs isoniazid, rifampicin, ethambutol and pyrazinamide in a cohort of patients with tuberculosis in Denmark and to determine the relationship between the concentrations and the clinical outcome. Methods: After 6-207 days of treatment (median 34 days) 2 h blood samples were collected from 32 patients with active tuberculosis and from three patients receiving prophylactic treatment. Plasma concentrations were determined using LC-MS/MS. Normal ranges were obtained from the literature. Clinical charts were reviewed for baseline characteristics and clinical status at 2, 4 and 6 months after the initiation of treatment. At a 1 year follow-up, therapy failure was defined as death or a relapse of tuberculosis. Results: Plasma concentrations below the normal ranges were frequently observed: isoniazid in 71%, rifampicin in 58%, ethambutol in 46%, pyrazinamide in 10% and both isoniazid and rifampicin in 45% of the patients. The plasma concentrations of isoniazid correlated inversely with the C-reactive protein level at the time of sampling (P = 0.001). During 1 year of follow-up, therapy failure occurred in five patients. Therapy failure occurred more frequently when the concentrations of isoniazid and rifampicin were both below the normal ranges (P = 0.013) and even more frequently when they were below the median 2 h drug concentrations obtained in the study (P = 0.005). Conclusions: At 2 h, plasma concentrations of isoniazid and rifampicin below the normal ranges were frequently observed. The inverse correlation between the plasma concentrations of isoniazid and C-reactive protein indicate a suboptimal treatment effect at standard dosing regimens. Dichotomization based on median 2 h drug concentrations was more predictive of outcome than dichotomization based on normal ranges.