Exposure (AUC(0-6 h)) to rifampicin was 53% lower in Indonesian patients with TB and DM, compared with patients with TB only. Patients with TB and DM who have a higher body weight may need a higher dose of rifampicin.

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 ⅐ h/liter) compared to the standard-dose group (48.5 mg ⅐ 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 >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.Each year, 8 million persons develop active tuberculosis (TB), and 2 to 3 million people die from this infectious disease. The treatment of TB is complicated by the length and complexity of currently available drug regimens, which invite problems of nonadherence, inadequate response, and resistance development. Therefore, a long-term goal for TB control has been to shorten the duration of treatment. This may possibly be achieved by increasing the dose of the pivotal TB drug rifampin, considering that early bactericidal activity studies in TB patients (8) and recent work in the mouse model (4) suggest that the typical 10-mg/kg of body weight dose of rifampin is rather low. A 50% increase in the rifampin dose may reduce the duration of treatment by one-third (4). Apart from these studies, we and others have found low 2-hour (peak) plasma concentrations of rifampin in TB patients treated with 10 mg/kg rifampin daily (7,17,18), which also suggests that a higher dose of rifampin merits further study.So far, only a few clinical data have been available with regard to the pharmacokinetics, tolerability, and effectiveness of drug regimens based on a higher dose of rifampin (6,14). Hence, we performed a pilot study in Indonesian patients in which we compared a higher dose (6...

Background. The long duration of the current tuberculosis (TB) treatment is demanding and warrants the development of new drugs. Moxifloxacin shows promising results and may be combined with rifampicin to shorten the duration of TB treatment. Rifampicin induces the phase II metabolic enzymes that are involved in the biotransformation of moxifloxacin. Therefore, the interaction between rifampicin and moxifloxacin should be investigated.Patients and methods. Nineteen Indonesian patients with pulmonary TB who were in the last month of their TB treatment completed a 1-arm, 2-period, fixed-order pharmacokinetic study. In phase 1 of the study, they received 400 mg of moxifloxacin every day for 5 days in addition to 450 mg of rifampicin and 600 mg of isoniazid 3 times per week. In phase 2 of the study, after a 1-month washout period, patients received moxifloxacin for another 5 days (without rifampicin and isoniazid). A 24-h pharmacokinetic curve for moxifloxacin was recorded on the last day of both study periods, and its pharmacokinetic parameters were evaluated for an interaction with rifampicin, using a bioequivalence approach.Results. Coadministration of moxifloxacin with rifampicin and isoniazid resulted in an almost uniform decrease in moxifloxacin exposure (in 18 of 19 patients). The geometric means for the ratio of phase 1 area under the curve to phase 2 area under the curve and for the ratio of phase 1 peak plasma concentration to phase 2 peak plasma concentration were 0.69 (90% confidence interval, 0.65-0.74) and 0.68 (90% confidence interval, 0.64-0.73), respectively. The median time to reach peak plasma concentration for moxifloxacin was prolonged from 1 h to 2.5 h when combined with rifampicin and isoniazid ( ). P p .003 Conclusions. Coadministration of moxifloxacin with intermittently administered rifampicin and isoniazid results in reduced moxifloxacin plasma concentrations, which is most likely the result of induced glucuronidation or sulphation by rifampicin. Further studies are warranted to evaluate the impact of the interaction on the outcome of TB treatment.

Altered pharmacokinetics of antituberculosis drugs may contribute to an increased risk of tuberculosis treatment failure for diabetic patients. We previously found that rifampin exposure was 2-fold lower in diabetic than in nondiabetic tuberculosis patients during the continuation phase of treatment. We now examined the influence of diabetes on the pharmacokinetics of antituberculosis drugs in the intensive phase of tuberculosis treatment, and we evaluated the effect of glycemic control. For this purpose, 18 diabetic and 18 gender-and body weight-matched nondiabetic tuberculosis patients were included in an Indonesian setting. Intensive pharmacokinetic sampling was performed for rifampin, pyrazinamide, and ethambutol at steady state. The bioavailability of rifampin was determined by comparing rifampin exposure after oral versus intravenous administration. Pharmacokinetic assessments were repeated for 10 diabetic tuberculosis patients after glycemic control. No differences in the areas under the concentrationtime curves of the drugs in plasma from 0 to 24 h postdose (AUC 0-24 ), the maximum concentrations of the drugs in plasma (C max ), the times to C max (T max ), and the half-lives of rifampin, pyrazinamide, and ethambutol were found between diabetic and nondiabetic tuberculosis patients in the intensive phase of tuberculosis treatment. For rifampin, oral bioavailability and metabolism were similar in diabetic and nondiabetic patients. The pharmacokinetic parameters of antituberculosis drugs were not correlated with blood glucose levels or glucose control. We conclude that diabetes does not alter the pharmacokinetics of antituberculosis drugs during the intensive phase of tuberculosis treatment. The reduced exposure to rifampin of diabetic patients in the continuation phase may be due to increased body weight and possible differences in hepatic induction. Further research is needed to determine the cause of increased tuberculosis treatment failure among diabetic patients.Diabetes mellitus (DM) is a well-known risk factor for tuberculosis (TB) (1, 3, 7), with prevalence rates among TB patients ranging from 10 to 30% (1,24,25). There is a rapid increase in the global prevalence of DM, especially in developing countries, where TB is highly endemic. It is estimated that by the year 2030, 80% of DM patients will live in the high-burden countries for TB (28). As a result, the number of TB patients with DM will increase further (19).Diabetes exerts a negative effect on TB treatment, especially among patients with poor glycemic control, with more treatment failure and more relapse than among TB patients in general (2,3,7,24). One of the possible underlying mechanisms could be altered pharmacokinetics of anti-TB drugs. Lower concentrations of anti-TB drugs in plasma have been associated with clinical failure and acquired drug resistance (11, 23). Our previous study showed that the mean exposure to rifampin (expressed as the area under the concentration-time curve of the drug in plasma from 0 to 6 h postdose [AUC 0-6 ])...

The study showed a high incidence of adverse events when a higher than standard dose of the new lopinavir/ritonavir tablets was combined with rifampicin. In the future, this drug combination should not be given to healthy volunteers. Liver function should be carefully monitored when rifampicin and lopinavir/ritonavir are combined in patients.

FIG. 1. Two-hour plasma rifampin concentrations after 4 weeks of TB treatment in Indonesian patients randomized to standard-dose (450 mg) or high-dose (600 mg) rifampin daily. Rifampin doses were combined with standard-dose isoniazid, pyrazinamide, and ethambutol. Depicted are data for individual patients (bullets) and means for both groups (horizontal bars). 822on May 10, 2018 by guest

Thirty-four patients treated concomitantly with lopinavir/ritonavir and rifampicin were evaluated. Overall, only 15% used the recommended increased dose of lopinavir/ritonavir. Of patients on a nonadjusted dose of lopinavir/ritonavir, 67% had a subtherapeutic lopinavir plasma concentration and 38% had a detectable viral load. Forty percent of patients on an increased dose of lopinavir/ritonavir prematurely stopped the drug combination because of adverse events. Combined use of lopinavir/ritonavir and rifampicin is challenging as it implies balancing between suboptimal efficacy and toxicity.

References 1. Nijland HM, Ruslami R, Stalenhoef JE, et al. Exposure to rifampicin is strongly reduced in patients with tuberculosis and type 2 diabetes. Clin Infect Dis 2006; 43:848-54. 2. McIlleron H, Wash P, Burger A, Norman J, Folb PI, Smith P. Determinants of rifampin, isoniazid, pyrazinamide, and ethambutol pharmacokinetics in a cohort of tuberculosis patients.