Pharmacokinetics of Antituberculosis Drugs in Pulmonary Tuberculosis Patients with Type 2 Diabetes

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 concentration-time 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]) and the mean peak concentration of the drug in plasma (C_max) were 2-fold lower in Indonesian TB patients with DM than in those without DM (14). In multivariate analyses, a higher body weight (P < 0.001), the presence of DM (P = 0.06), and higher blood glucose levels (P = 0.016) contributed to lower plasma rifampin concentrations. These results suggested that heavier diabetic TB patients may need to be treated with a higher dose of rifampin and that glycemic control may increase drug concentrations.In our previous study, TB patients with and without DM were not matched for weight (6, 15); only rifampin was measured; and limited sampling points were used to assess the pharmacokinetics of this drug. We have therefore performed an in-depth follow-up study in which TB patients with and without DM were matched for weight in order to enable disentangling of the effects of DM and weight on plasma drug concentrations. Furthermore, rifampin, pyrazinamide, and ethambutol were studied, and intensive pharmacokinetic sampling was performed. The first objective of the study was to compare the pharmacokinetics of rifampin, pyrazinamide, and ethambutol between weight-matched diabetic and nondiabetic TB patients. The second objective was to elaborate the possible mechanism of the alteration of pharmacokinetics of rifampin, and the third was to evaluate the effect of glycemic control on the pharmacokinetics of anti-TB drugs in diabetic TB patients.