Pharmacokinetics and tolerability of a higher rifampin dose versus the standard dose in pulmonary tuberculosis patients.
Rifampin is a key drug for tuberculosis (TB) treatment. The available data suggest that the currently applied 10-mg/kg of body weight dose of rifampin may be too low and that increasing the dose may shorten the treatment duration. A double-blind randomized phase II clinical trial was performed to investigate the effect of a higher dose of rifampin in terms of pharmacokinetics and tolerability. Fifty newly diagnosed adult Indonesian TB patients were randomized to receive a standard (450-mg, i.e., 10-mg/kg in Indonesian patients) or higher (600-mg) dose of rifampin in addition to other TB drugs. A full pharmacokinetic curve for rifampin, pyrazinamide, and ethambutol was recorded after 6 weeks of daily TB treatment. Tolerability was assessed during the 6-month treatment period. The geometric means of exposure to rifampin (area under the concentration-time curve from 0 to 24 h [AUC(0-24)]) were increased by 65% (P < 0.001) in the higher-dose group (79.7 mg.h/liter) compared to the standard-dose group (48.5 mg.h/liter). Maximum rifampin concentrations (C(max)) were 15.6 mg/liter versus 10.5 mg/liter (49% increase; P < 0.001). The percentage of patients for whom the rifampin C(max) was > or =8 mg/liter was 96% versus 79% (P = 0.094). The pharmacokinetics of pyrazinamide and ethambutol were similar in both groups. Mild (grade 1 or 2) hepatotoxicity was more common in the higher-dose group (46 versus 20%; P = 0.054), but no patient developed severe hepatotoxicity. Increasing the rifampin dose was associated with a more than dose-proportional increase in the mean AUC(0-24) and C(max) of rifampin without affecting the incidence of serious adverse effects. Follow-up studies are warranted to assess whether high-dose rifampin may enable shortening of TB treatment.
Ruslami
Rovina
R
Department of Pharmacology, Medical Faculty, University of Padjadjaran, Bandung, Indonesia.
Nijland
Hanneke M J
HM
Alisjahbana
Bachti
B
Parwati
Ida
I
van Crevel
Reinout
R
Aarnoutse
Rob E
RE
D000293:Adolescent; D000328:Adult; D000904:Antibiotics, Antitubercular / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000995:Antitubercular Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004361:Drug Tolerance; D004977:Ethambutol / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011718:Pyrazinamide / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D013902:Radiography, Thoracic; D012293:Rifampin / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000097:blood / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000382:microbiology
D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D011718:Pyrazinamide; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin