Pharmacokinetics of pyrazinamide during the initial phase of tuberculous meningitis treatment.

Tuberculous meningitis (TBM) is the most severe manifestation of tuberculosis. Pyrazinamide (PZA) is a pivotal antituberculous drug, but its dose has not been optimised for TBM. The aims of this study were to describe the pharmacokinetics of PZA during TBM treatment, to identify predictors of PZA exposure and to assess relationships between PZA dose and exposures in plasma and CSF. Plasma PZA pharmacokinetic data were assessed on Days 2 and 10 of treatment in 52 adult TBM patients. A CSF-to-plasma concentration ratio was determined on Day 2. Predictors of plasma PZA exposure, correlation between plasma and CSF exposures, and prediction of CSF concentrations based on dose and plasma exposure were evaluated. The geometric mean plasma PZA exposure (AUC0-24) and peak concentration (Cmax) on Day 2 were 709 h·mg/L and 59 mg/L following a median dose of 33.3 mg/kg/day; AUC0-24 on Day 10 (523 h·mg/L) was lower (P < 0.001). Dose and BMI correlated with AUC0-24 and Cmax. The CSF concentration at 3-6 h was 42 mg/L and the CSF-to-plasma ratio was 90%. AUC0-24, Cmax and CSF concentration were highly correlated. CSF concentration could be predicted based on dose and various plasma exposure measures with <5% bias and <21% imprecision. Exposure to PZA decreases during the first days of TBM treatment, possibly due to the evolving inductive effect of rifampicin. PZA penetrates well in CSF. The association between PZA dose and exposures in plasma and CSF provides a rationale to study higher PZA doses for TBM.

Pharmacokinetics, Tolerability, and Bacteriological Response of Rifampin Administered at 600, 900, and 1,200 Milligrams Daily in Patients with Pulmonary Tuberculosis.

In a multiple-dose-ranging trial, we previously evaluated higher doses of rifampin in patients for 2 weeks. The objectives of the current study were to administer higher doses of rifampin for a longer period to compare the pharmacokinetics, safety/tolerability, and bacteriological activity of such regimens. In a double-blind, randomized, placebo-controlled, phase II clinical trial, 150 Tanzanian patients with tuberculosis (TB) were randomized to receive either 600 mg (approximately 10 mg/kg of body weight), 900 mg, or 1,200 mg rifampin combined with standard doses of isoniazid, pyrazinamide, and ethambutol administered daily for 2 months. Intensive pharmacokinetic sampling occurred in 63 patients after 6 weeks of treatment, and safety/tolerability was assessed. The bacteriological response was assessed by culture conversion in liquid and solid media. Geometric mean total exposures (area under the concentration-versus-time curve up to 24 h after the dose) were 24.6, 50.8, and 76.1 mg · h/liter in the 600-mg, 900-mg, and 1,200-mg groups, respectively, reflecting a nonlinear increase in exposure with the dose (P < 0.001). Grade 3 adverse events occurred in only 2 patients in the 600-mg arm, 4 patients in the 900-mg arm, and 5 patients in the 1,200-mg arm. No significant differences in the bacteriological response were observed. Higher daily doses of rifampin (900 and 1,200 mg) resulted in a more than proportional increase in rifampin exposure in plasma and were safe and well tolerated when combined with other first-line anti-TB drugs for 2 months, but they did not result in improved bacteriological responses in patients with pulmonary TB. These findings have warranted evaluation of even higher doses of rifampin in follow-up trials. (This study has been registered at ClinicalTrials.gov under identifier NCT00760149.).

Exposure to total and protein-unbound rifampin is not affected by malnutrition in Indonesian tuberculosis patients.

Nutritional status may have a profound impact on the pharmacokinetics of drugs, yet only few data are available for tuberculosis (TB) drugs. As malnutrition occurs frequently among TB patients, we assessed the effect of malnutrition on the steady-state pharmacokinetics of total and protein-unbound rifampin during the intensive phase of TB treatment. In a descriptive pharmacokinetic study in Bandung, Indonesia, patients received a fixed standard rifampin dose of 450 mg once daily during the intensive phase of TB treatment. A full pharmacokinetic curve for rifampin was recorded, and total and unbound concentrations of rifampin were analyzed in all samples. Rifampin pharmacokinetic parameters were compared between severely malnourished (BMI of <16.0 kg/m(2)), malnourished (BMI of <18.5 kg/m(2)), and well-nourished (BMI of ≥18.5 kg/m(2)) individuals. No difference in total and protein-unbound pharmacokinetic parameters between severely malnourished (n = 7), malnourished (n = 11), and well-nourished (n = 25) patients could be demonstrated. In addition, no significant correlation between BMI and exposure (area under the concentration-time curve from 0 to 24 h [AUC0-24] and maximum concentration of drug in serum [Cmax]) was found. Females had significantly higher total AUC0-24 (geometric mean, 59.2 versus 48.2 h · mg/liter; P = 0.02) and higher unbound AUC0-24 (geometric mean, 6.2 versus 4.8 h · mg/liter; P = 0.02) than males. Overall, a marked 2-fold interindividual variation in the free fraction was observed (7.6 to 15.0%; n = 36). Nutritional status and BMI do not appear to have a major effect on total and protein-unbound pharmacokinetic parameters of rifampin in Indonesian subjects. The large interindividual variability in the free fraction of rifampin suggests that protein-unbound rather than total rifampin concentrations should preferably be used to study exposure-response relationships.