Determinants of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol Pharmacokinetics in a Cohort of Tuberculosis Patients

Abstract

Evaluation of sources of pharmacokinetic variation can facilitate optimization of tuberculosis treatment regimens by identification of avoidable sources of variation and of risk factors for low or high drug concentrations in patients. Our objective was to describe the pharmacokinetics of rifampin, isoniazid, pyrazinamide, and ethambutol in a cohort of tuberculosis patients established on first-line treatment regimens and to evaluate the determinants of pharmacokinetic variation. Plasma concentration-time profiles were determined for each of the drugs in 142 patients with drug-sensitive pulmonary tuberculosis after 2 months of daily treatment in hospital. Pharmacokinetic measures were described by noncompartmental analysis. Multiple linear regression was used to evaluate the patient and the treatment factors associated with variation of the area under the concentration-time curve from 0 to 8 h. Several factors independently associated with variations in antituberculosis drug concentrations were identified: human immunodeficiency virus infection was associated with 39% and 27% reductions for rifampin and ethambutol, respectively; formulation factors were determinants of rifampin and isoniazid bioavailability; female patients had increased rifampin and isoniazid concentrations but reduced ethambutol concentrations; older patients had higher levels of isoniazid and ethambutol; patients with a history of previous antituberculosis treatment had lower ethambutol concentrations; and the dose per kilogram of body weight was associated with the concentrations of all four agents. Further studies are required to assess the implications of variations in antituberculosis drug concentrations for efficacy and safety before decisions are made to change the dosing strategy in patients at risk.

The pharmacokinetics of enteral antituberculosis drugs in patients requiring intensive care

“…[19] Furthermore, McIlleron and co-workers demonstrated a wide variation in plasma concentrations of rifampicin, with almost 70% of the study group at the lower end (<8 µg/l) and 22% at the very low end (<4 µg/l) of the therapeutic range. [20] Kimerling et al reported very similar findings, 64% of subjects having levels below 8 µg/l for rifampicin. [21] In a cohort of patients, the majority of whom were HIV-infected, Chideya et al …”

Simultaneous determination of isoniazid and pyrazinamide in plasma by high performance liquid chromatography

“…Moussa et al [11] determined that the INH concentration in 3 h post-dose samples was below the reference range in 54 % of 13 TB patients. Our results, together with the results of other studies [18,19], indicate the importance of analyzing a series of blood samples to obtain the maximum blood concentrations of INH and PZA. Relying on one sample taken at a specific time, such as the 2 or 3 h post dose, is likely to yield a false high percentage of patients with low levels of these drugs, particularly INH.…”

“…McIlleron et al [18] reported that the median C max of INH was 6.5 mg/L, and only 2 % of 142 patients had C max of INH level less than 3 mg/L. The median C max of PZA was 52.7 mg/L, and only one patient (0.7 %) had C max of PZA less than 20 mg/L.…”

“…In this method, no differences between these concentrations were observed; thus, the lowest concentration (10 %) was selected. CS choices for INH and PZA were made based on their ranges in TB patients found in other studies [5][6][7]18,19]. QCS concentrations were selected based on the recommendations of the FDA guideline for bioanalytical method validation [20].…”

Tuberculous Meningitis in Adults: A Review of a Decade of Developments Focusing on Prognostic Factors for Outcome

“…In particular, CSF penetration of rifampicin, the key drug in TBM treatment, is poor, as is that of ethambutol and streptomycin [75][76][77]. Isoniazid and pyrazinamide penetrate more readily [78,79].…”