Chemical Class:
Name of Target:
RNA Polymerase
Rifampin is a pivotal drug for the treatment of tuberculosis. The U.S. Food and Drug Administration approved rifampin in 1971 and several trials showed that rifampin-containing regimens were very effective. In combination with pyrazinamide, it became possible to shorten the duration of treatment to 6 months. Virtually all of the studies that support these recommendations used a 10 mg/kg dose of rifampin , but a dose-finding study with an assessment of the maximum tolerated dose was never performed. The recommended dose was chosen on the basis that it was effective at the lowest cost and limited by fear of adverse effects. Boeree and others have performed studies in patients with tuberculosis to establish the maximum tolerated dose, to assess the incidence and severity of adverse events,to describe the pharmacokinetics, and to measure the bactericidal effect of higher doses of rifampin. ____________________________________________________________ From Microbe 2017: The PanACEA HIGHRIF1 trial (Boeree et al. AJRCCM, 2015) evaluated up to 40 mg/kg rifampicin (RIF) in tuberculosis (TB) patients. No statistically significant dose-response relationship was detected using conventional statistical methods. The exposure-response (ER) relationship between RIF and colony forming unit (CFU) and time-to-positivity (TTP) in mycobacterial growth incubator tube (MGIT) using non-linear mixed effects modeling was explored. Analysis was performed in NONMEM 7.3. For CFU a RIF pharmacokinetic model (Svensson et al. PAGE 25, 2016) was linked to the Multistate TB Pharmacometric (MTP) model (Clewe et al. JAC, 2016, Svensson and Simonsson CPT:PSP, 2016) and ER relationships were estimated between RIF and kill or growth of fast- (F), slow- (S) and non-multiplying (N) bacteria. For MGIT a time-to-event model (Svensson and Karlsson PAGE 25, 2016) was used. Model selection was guided by the likelihood ratio test and visual predictive checks. All 83 patients were included in the analysis. Statistically significant ER relationships were defined between RIF and fall in CFU and increase in MGIT. RIF was found to affect F, S and N bacteria. In contrast to earlier analyses using conventional statistical methods, statistically significant ER relationships were found between RIF and fall in bacterial load as measure by CFU and MGIT. This provides further evidence that high dose RIF are more effective and should be tested in pivotal clinical trials.!/4358/presentation/6176