Safety and bactericidal activity of rifalazil in patients with pulmonary tuberculosis.

Abstract

Rifalazil, also known as KRM-1648 or benzoxazinorifamycin, is a new semisynthetic rifamycin with a long half-life of approximately 60 h. Rifalazil has potent bactericidal activity against Mycobacterium tuberculosis in vitro and in animal models of tuberculosis (TB). Prior studies in healthy volunteers showed that once-weekly doses of 25 to 50 mg of rifalazil were well tolerated. In this randomized, open-label, active-controlled phase II clinical trial, 65 subjects with sputum smear-positive pulmonary TB received one of the following regimens for the first 2 weeks of therapy: 16 subjects received isoniazid (INH) (5 mg/kg of body weight) daily; 16 received INH (5 mg/kg) and rifampin (10 mg/kg) daily; 17 received INH (5 mg/kg) daily plus 10 mg of rifalazil once weekly; and 16 received INH (5 mg/kg) daily and 25 mg of rifalazil once weekly. All subjects were then put on 6 months of standard TB therapy. Pretreatment and day 15 sputum CFU of M. tuberculosis were measured to assess the bactericidal activity of each regimen. The number of drug-related adverse experiences was low and not significantly different among treatment arms. A transient decrease in absolute neutrophil count to less than 2,000 cells/mm(3) was detected in 10 to 20% of patients in the rifalazil- and rifampin-containing treatment arms without clinical consequences. Decreases in CFU counts were comparable among the four treatment arms; however, the CFU results were statistically inconclusive due to the variability in the control arms. Acquired drug resistance did not occur in any patient. Studies focused on determining a maximum tolerated dose will help elucidate the full anti-TB effect of rifalazil.

• Authors: R Dietze, L Teixeira, L M Rocha, M Palaci, J L Johnson, C Wells, L Rose, K Eisenach, J J Ellner
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 45 Issue 7 Pg. 1972-6 (Jul 2001) ISSN: 0066-4804 [Print] United States
• PMID: 11408210 (Publication Type: Clinical Trial, Clinical Trial, Phase II, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibiotics, Antitubercular
• Antitubercular Agents
• Rifamycins
• KRM 1648
• Isoniazid

Topics

• Adolescent
• Adult
• Antibiotics, Antitubercular (adverse effects, pharmacokinetics, therapeutic use)
• Antitubercular Agents (therapeutic use)
• Colony Count, Microbial
• Female
• Hematologic Tests
• Humans
• Isoniazid (therapeutic use)
• Kidney Function Tests
• Liver Function Tests
• Male
• Rifamycins (adverse effects, pharmacokinetics, therapeutic use)
• Tuberculosis, Pulmonary (drug therapy, metabolism, microbiology)