Intestinal permeability and malabsorption of rifampin and isoniazid in active pulmonary tuberculosis

Pinheiro, Valéria Goes Ferreira; Ramos, Lysiane M.A; Monteiro, Helena Serra Azul; E, Barroso; Bushen, Oluma Y.; Façanha, Mônica Cardoso; Peloquin, Charles A.; Guerrant, Richard L.; Lima, Aldo A. M.

doi:10.1590/s1413-86702006000600003

Cited by 52 publications

(51 citation statements)

References 24 publications

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“…HIV is known to target the small intestine, especially the gutassociated lymphoid tissue, and HIV-mediated enteropathy is associated with malabsorption (27). Decrease in the functional absorptive area of the intestine has been associated with reduced TB drug availability (28)(29)(30)(31). The recovery mechanism whereby nutritional supplementation may restore the pathophysiology and immunological changes is not explained and warrants further studies (26).…”

Section: Discussionmentioning

confidence: 99%

Nutritional Supplementation Increases Rifampin Exposure among Tuberculosis Patients Coinfected with HIV

Jeremiah

Denti

Cosson

et al. 2014

Antimicrob Agents Chemother

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f Nutritional supplementation to tuberculosis (TB) patients has been associated with increased weight and reduced mortality, but its effect on the pharmacokinetics of first-line anti-TB drugs is unknown. 2 ) were randomized to receive nutritional supplementation during the intensive phase of TB treatment. Rifampin plasma concentrations were determined after 1 week and 2 months of treatment. The effects of nutritional supplementation, HIV, time on treatment, body weight, and SLCO1B1 rs4149032 genotype were examined using a population pharmacokinetic model. The model adjusted for body size via allometric scaling, accounted for clearance autoinduction, and detected an increase in bioavailability (؉14%) for the patients in the continuation phase. HIV coinfection in patients not receiving the supplementation was found to decrease bioavailability by 21.8%, with a median maximum concentration of drug in serum (C max ) and area under the concentration-time curve from 0 to 24 h (AUC 0 -24 ) of 5.6 g/ml and 28.6 g · h/ml, respectively. HIV-coinfected patients on nutritional supplementation achieved higher C max and AUC 0 -24 values of 6.4 g/ml and 31.6 g · h/ml, respectively, and only 13.3% bioavailability reduction. No effect of the SLCO1B1 rs4149032 genotype was observed. In conclusion, nutritional supplementation during the first 2 months of TB treatment reduces the decrease in rifampin exposure observed in HIV-coinfected patients but does not affect exposure in HIV-uninfected patients. If confirmed in other studies, the use of defined nutritional supplementation in HIV-coinfected TB patients should be considered in TB control programs. (This study has the controlled trial registration number ISRCTN 16552219.)

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Section: Discussionmentioning

confidence: 99%

Nutritional Supplementation Increases Rifampin Exposure among Tuberculosis Patients Coinfected with HIV

Jeremiah

Denti

Cosson

et al. 2014

Antimicrob Agents Chemother

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

McLeay

Vis

Heeswijk

et al. 2014

Antimicrob Agents Chemother

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Bedaquiline is a novel agent for the treatment of pulmonary multidrug-resistant Mycobacterium tuberculosis infections, in combination with other agents. The objective of this study was to develop a population pharmacokinetic (PK) model for bedaquiline to describe the concentration-time data from phase I and II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant tuberculosis (TB). A total of 5,222 PK observations from 480 subjects were used in a nonlinear mixed-effects modeling approach. The PK was described with a 4-compartment disposition model with dual zero-order input (to capture dual peaks observed during absorption) and long terminal half-life (t 1/2 ). The model included between-subject variability on apparent clearance (CL/F), apparent central volume of distribution (V c /F), the fraction of dose via the first input, and bioavailability (F). Bedaquiline was widely distributed, with apparent volume at steady state of >10,000 liters and low clearance. The long terminal t 1/2 was likely due to redistribution from the tissue compartments. The final covariate model adequately described the data and had good simulation characteristics. The CL/F was found to be 52.0% higher for subjects of black race than that for subjects of other races, and V c /F was 15.7% lower for females than that for males, although their effects on bedaquiline exposure were not considered to be clinically relevant. Small differences in F and CL/F were observed between the studies. The residual unexplained variability was 20.6% and was higher (27.7%) for long-term phase II studies.

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“…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.…”

Section: Fig 2 Isoniazid Plasma Concentration Over Time (0 -24 Hourmentioning

confidence: 99%

“…[7] Interestingly, evidence suggests that the functional absorptive area of the intestines of patients with tuberculosis is also decreased when compared with healthy volunteers, which in turn results in decreased absorption. [8] There are currently no published studies on absorption rates and pharmacokinetic patterns of anti-TB drugs in patients requiring intensive care. The aim of this pilot study was therefore to assess whether therapeutic plasma drug concentrations are achieved following nasogastric administration of first-line fixed-dose combination standard anti-TB treatment in critically ill patients.…”

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confidence: 99%

The pharmacokinetics of enteral antituberculosis drugs in patients requiring intensive care

et al. 2013

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Background. There is a paucity of data on the pharmacokinetics of fixed-dose combination enteral antituberculosis treatment in critically ill patients. Objectives. To establish the pharmacokinetic profile of a fixed-dose combination of rifampicin, isoniazid, pyrazinamide and ethambutol given according to weight via a nasogastric tube to patients admitted to an intensive care unit (ICU). Methods. We conducted a prospective, observational study on 10 patients (mean age 32 years, 6 male) admitted to an ICU and treated for tuberculosis (TB). Serum concentrations of the drugs were determined at eight predetermined intervals over 24 hours by means of highperformance liquid chromatography. Results. The therapeutic maximum plasma concentration (C max ) for rifampicin at time to peak concentration was achieved in only 4 patients, whereas 2 did not achieve therapeutic C max for isoniazid. No patient reached sub-therapeutic C max for pyrazinamide (6 were within and 4 above therapeutic range). Three patients reached sub-therapeutic C max for ethambutol, and 6 patients were within and 1 above the therapeutic range. Patients with a sub-therapeutic rifampicin level had a higher mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score (p=0.03) and a lower estimated glomerular filtration rate (GFR) (p=0.03). Conclusions. A fixed-dose combination tablet, crushed and mixed with water, given according to weight via a nasogastric tube to patients with TB admitted to an ICU resulted in sub-therapeutic rifampicin plasma concentrations in the majority of patients, whereas the other drugs had a more favourable pharmacokinetic profile. Patients with a sub-therapeutic rifampicin concentration had a higher APACHE II score and a lower estimated GFR, which may contribute to suboptimal outcomes in critically ill patients. Studies in other settings have reported similar proportions of patients with 'sub-therapeutic' rifampicin concentrations.

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Intestinal permeability and malabsorption of rifampin and isoniazid in active pulmonary tuberculosis

Cited by 52 publications

References 24 publications

Nutritional Supplementation Increases Rifampin Exposure among Tuberculosis Patients Coinfected with HIV

Nutritional Supplementation Increases Rifampin Exposure among Tuberculosis Patients Coinfected with HIV

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

The pharmacokinetics of enteral antituberculosis drugs in patients requiring intensive care

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