Serum Concentrations of Rifampin, Isoniazid, and Intestinal Absorption, Permeability in Patients with Multidrug Resistant Tuberculosis

Abstract

This study evaluates the serum concentrations of rifampin (RMP), isoniazid (INH), and intestinal barrier function in patients with multidrug-resistant tuberculosis (MDR-TB), drug susceptible tuberculosis (DS-TB), and health volunteers (HC; controls). Peak serum concentrations of RMP were significantly lower in MDR-TB and DS-TB as compared with HC (odds ratio [OR] = 3.125, confidence interval [CI] [1.037-9.418] and OR = 4.025, CI [1.207-13.418], respectively). The INH peak serum concentration was not significantly different between MDR-TB versus DS-TB or DS-TB versus HC. The percent of mannitol excretion was significantly lower in the MDR-TB group compared with DS-TB (13.18 versus 16.03, analysis of covariance [ANCOVA], P = 0.0369) and compared with HC (13.18 versus 16.61, ANCOVA, P = 0.0291) the other study groups. These data suggested a lower peak serum concentration of RMP for both MDR-TB and DS-TB as compared with the HC group. The data also showed a lower intestinal area of absorption in patients with tuberculosis and even worse in MDR-TB.

Pharmacokinetics of Rifampin and Isoniazid in Tuberculosis-HIV-Coinfected Patients Receiving Nevirapine- or Efavirenz-Based Antiretroviral Treatment

“…Tuberculosis and HIV infection were found to alter absorption and, consequently, decrease antituberculosis drug concentrations (11,22,23,37). Interestingly, Barroso et al (38) compared rifampin and isoniazid C max levels in healthy volunteers and patients with susceptible tuberculosis. C max levels of rifampin were higher in healthy controls (5.7 mg/liter) than in tuberculosis-infected patients (2.11 mg/liter), whereas C max levels of isoniazid were similar in healthy controls and tuberculosis patients (3.26 mg/liter and 2.85 mg/liter, respectively).…”

Population Pharmacokinetics of Bedaquiline (TMC207), a Novel Antituberculosis Drug

“…Reduced intestinal permeability has been observed in patients with TB, which may reduce bioavailability and thus explain lower exposure to certain anti-TB drugs (15,16). Barroso et al (15) evaluated intestinal barrier function and serum concentrations of RIF and INH in outpatients with MDR-TB, DS-TB, and healthy subjects, and they observed a significantly lower intestinal area of absorption (as measured by the urinary excretion rate of orally administered mannitol) and lower RIF concentrations in patients with MDR-TB than those of patients with DS-TB or of healthy subjects (15). In a population pharmacokinetics analysis of another TB drug, ethionamide, the average exposure was about 50% lower in patients with TB than that in healthy volunteers, which was explained by a lower bioavailability of ethionamide in the patients (17).…”

The pharmacokinetics of enteral antituberculosis drugs in patients requiring intensive care

“…Previous studies demonstrated that there is a decrease in functional absorptive area of the intestines in patients with TB. [8,23] This is especially true in patients with multidrug-resistant TB. [23] It has been demonstrated that intestinal paracellular absorption in patients with active pulmonary TB is markedly decreased, but that this is unlikely to contribute significantly to lower plasma levels, as it represents less than 5% of the total absorptive area of the small intestine.…”

“…[8,23] This is especially true in patients with multidrug-resistant TB. [23] It has been demonstrated that intestinal paracellular absorption in patients with active pulmonary TB is markedly decreased, but that this is unlikely to contribute significantly to lower plasma levels, as it represents less than 5% of the total absorptive area of the small intestine. [24] The patients in our study group were given rifampicin in a combination tablet either on an empty stomach with the addition of an antacid (sucralfate) or while given continuous feeds.…”