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 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.

FIG. 1.

Study design. R, rifampin at 450 mg daily; Z, pyrazinamide at 1,500 mg daily; E, ethambutol at 750 mg daily; p.o., per os; i.v., intravenous; PK, pharmacokinetic assessment. PK I took place 2 weeks after the start of TB treatment, and all TB drugs were administered per os. PK II was performed the day after PK I, and 450 mg of rifampin was administered intravenously by continuous infusion for 90 min. PK III was performed for 10 diabetic TB patients 3 weeks after normal blood glucose levels were achieved. For glycemic control, subcutaneous (s.c.) insulin injection was used, with the dose adjusted in order to normalize blood glucose within 2 to 3 weeks; all anti-TB drugs were administered per os.

FIG. 2.

Mean steady-state plasma concentration-time profiles of antituberculosis drugs. Mean steady-state plasma concentration-time profiles of rifampin (n = 17) (a), pyrazinamide (n = 18) (b), and ethambutol (n = 17) (c) in TB patients with (▪) and without (○) DM are shown.