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

Abstract

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 ])...

Effect of Diabetes Mellitus on Rifampicin Peak Serum Concentration

“…The mean age (48.7 y) of the male patients was greater when compared to a similar study conducted by Mendez (2012) [14]. The mean age of PTB patients with diabetes and without diabetes in the present study was in contrast to that conducted by Ruslami et al (2010) [15]. However, our results were similar to Ruslami et al when the statistical significance in body weight between these groups was analyzed [15].…”

“…The mean age of PTB patients with diabetes and without diabetes in the present study was in contrast to that conducted by Ruslami et al (2010) [15]. However, our results were similar to Ruslami et al when the statistical significance in body weight between these groups was analyzed [15]. Exposure to rifampicin has been reported to be two-fold lower in diabetic than in non-diabetic patients with tuberculosis during the continuation phase of treatment [14].…”

“…Clinical studies suggest that hyperglycemic state decreases the release of gastric acid from parietal cells and thereby increases gastric pH. Being highly pH dependent for solubility and well absorbed from an acidic pH, a shift in the gastric pH due to hyperglycemia delays rifampicin absorption and thereby tend to prolong the tmax and decrease the Cmax [15]. In addition, gastrointestinal ailments such as gastroparesis which are common in chronic diabetics may either delay or impair absorption of rifampicin leading to decreased systemic availability [17].…”

Comparative study of the mutant prevention concentrations of vancomycin alone and in combination with levofloxacin, rifampicin and fosfomycin against methicillin-resistant Staphylococcus epidermidis

“…The top concentration prepared for fosfomycin MPC determination was 64 mg ml À1 , which is double the resistant or susceptible breakpoint concentration of Staphylococcus to fosfomycin (32 mg ml À1 ) according to EUCAST. 17 The concentrations of levofloxacin (2 mg ml À1 ) and rifampicin (2 or 4 mg ml À1 ) used in combination with vancomycin reflect their mean serum concentrations at steady state in healthy adults 21 and adult pulmonary tuberculosis patients, 22,23 respectively. The concentration of fosfomycin (32 mg ml À1 ) used in combination with vancomycin equals the susceptible breakpoint concentration of staphylococci but is far below the mean serum concentrations at steady state according to currently recommended dosing regimens.…”

An Antitubercular Therapy Induced-Hepatotoxicity Case with Diffuse Ascites

“…This is considered to be related to the change in antituberculosis drug pharmacokinetics in diabetic patients. In a study by Ruslami and colleagues, it was observed that there was no difference between diabetic and non-diabetic patients in rifampicin, pyrazinamid and ethambutol pharmacokinetics in the intensive phase of treatment; but in the continued phase of treatment, pharmacokinetics of rifampicin were changed and its blood concentration was decreased (24)(25)(26). Although this can be explained by weight gain and other possible causes, further studies are needed.…”