Noninferiority of the 4-month regimen to the standard regimen with respect to the primary efficacy end point was not shown. (Funded by the Special Program for Research and Training in Tropical Diseases and others; ClinicalTrials.gov number, NCT00216385.).

The 4-month regimen of rifampin was not inferior to the 9-month regimen of isoniazid for the prevention of active tuberculosis and was associated with a higher rate of treatment completion and better safety. (Funded by the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council; ClinicalTrials.gov number, NCT00931736 .).

The study results support the use of the short regimen recently recommended by the World Health Organization. Its high level of success even among HIV-positive patients promises substantial improvements in TB control.

The currently recommended doses of rifampin are believed to be at the lower end of the dose-response curve. Rifampin induces its own metabolism, although the effect of dose on the extent of autoinduction is not known. This study aimed to investigate rifampin autoinduction using a semimechanistic pharmacokinetic-enzyme turnover model. Four different structural basic models were explored to assess whether different scaling methods affected the final covariate selection procedure. Covariates were selected by using a linearized approach. The final model included the allometric scaling of oral clearance and apparent volume of distribution. Although HIV infection was associated with a 30% increase in the apparent volume of distribution, simulations demonstrated that the effect of HIV on rifampin exposure was slight. Model-based simulations showed close-to-maximum induction achieved after 450-mg daily dosing, since negligible increases in oral clearance were observed following the 600-mg/day regimen. Thus, dosing above 600 mg/day is unlikely to result in higher magnitudes of autoinduction. In a typical 55-kg male without HIV infection, the oral clearance, which was 7.76 liters · h ؊1 at the first dose, increased 1.82-and 1.85-fold at steady state after daily dosing with 450 and 600 mg, respectively. Corresponding reductions of 41 and 42%, respectively, in the area under the concentration-versus-time curve from 0 to 24 h were estimated. The turnover of the inducible process was estimated to have a half-life of approximately 8 days in a typical patient. Assuming 5 half-lives to steady state, this corresponds to a duration of approximately 40 days to reach the induced state for rifampin autoinduction. Rifampin is an indispensable constituent of first-line therapy used to treat drug-susceptible Mycobacterium tuberculosis. During the 2-month intensive phase of standard short-course antituberculosis treatment, patients receive rifampin together with isoniazid, pyrazinamide, and ethambutol. Rifampin and isoniazid are given for a further 4-month continuation phase, completing the 6-month treatment regimen. Isoniazid is responsible for killing the majority of organisms within the first 2 days of treatment. From the third to the seventh day of treatment, rifampin and pyrazinamide continue the bactericidal function (30), while ethambutol protects against the development of rifampin resistance in the event of preexisting isoniazid resistance (8). The ability of rifampin to eradicate persisting organisms has allowed the shortening of treatment from 12 to 6 months (43).Rifampin is a potent activator of the nuclear pregnane X receptor (PXR), which regulates the transcription of multiple drugmetabolizing enzymes and drug transporters (9, 13). Although the exact mechanism is not known, following chronic intravenous or oral dosing, rifampin induces its own metabolism by increasing its systemic and presystemic clearances (27,31). This effect might, in part, be attributed to the PXR-mediated induction of P-glycoprotein (P-gp), a trans-mem...

Among children under the age of 18 years, treatment with 4 months of rifampin had similar rates of safety and efficacy but a better rate of adherence than 9 months of treatment with isoniazid. (Funded by the Canadian Institutes of Health Research and Conselho Nacional de Pesquisa; ClinicalTrials.gov number, NCT00170209 .).