Oral Bioavailability of Rifampicin, Isoniazid, Ethambutol, and Pyrazinamide in a 4-Drug Fixed-Dose Combination Compared With the Separate Formulations in Healthy Chinese Male Volunteers

Xu, Jian; Jin, Haixia; Zhu, Hui; Zheng, Meiqin; Wang, Bin; Liu, Chengcheng; Chen, Ming-Ting; Zhou, Lin; Zhao, Weijie; Fu, Ling; Lu, Yu

doi:10.1016/j.clinthera.2013.01.003

Cited by 32 publications

(24 citation statements)

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“…The addition of E to the RHZ regimen reduced the risk of further resistance in patients with initial resistance to H alone, in those with simultaneous resistance to H and Z, and in those with resistance to R alone (which is rare) but has no protective effect in cases of simultaneous resistance to H and R (i.e., MDR-TB). 20 In addition, a bioavailability study conducted in 2013 demonstrated a lack of bioequivalence between FDC and separate drug formulations of H. 26 These data, together with the aforementioned bioavailability problems affecting FDC formulations of R and the aforementioned reduction in the doses of H and Z, underscore the importance of conducting bioequivalence and bioavailability studies of FDC formulations of tuberculosis therapy. 19 - 21 The increase in resistance appears to be associated with malfunctioning tuberculosis control programs.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the impact that the changes in tuberculosis treatment implemented in Brazil in 2009 have had on disease control in the country

2017

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Objective:To analyze the impact that the 2009 changes in tuberculosis treatment in Brazil had on the rates of cure, tuberculosis recurrence, mortality, treatment abandonment, and multidrug-resistant tuberculosis (MDR-TB). Methods:An ordinary least squares regression model was used in order to perform an interrupted time series analysis of secondary data collected from the Brazilian Tuberculosis Case Registry Database for the period between January of 2003 and December of 2014. Results:The 2009 changes in tuberculosis treatment in Brazil were found to have no association with reductions in the total number of cases (β = 2.17; 95% CI: −3.80 to 8.14; p = 0.47) and in the number of new cases (β = −0.97; 95% CI: −5.89 to 3.94; p = 0.70), as well as having no association with treatment abandonment rates (β = 0.40; 95% CI: −1.12 to 1.93; p = 0.60). The changes in tuberculosis treatment also showed a trend toward an association with decreased cure rates (β = −4.14; 95% CI: −8.63 to 0.34; p = 0.07), as well as an association with increased mortality from pulmonary tuberculosis (β = 0.77; 95% CI: 0.16 to 1.38; p = 0.01). Although there was a significant increase in MDR-TB before and after the changes (p < 0.0001), there was no association between the intervention (i.e., the changes in tuberculosis treatment) and the increase in MDR-TB cases. Conclusions:The changes in tuberculosis treatment were unable to contain the decrease in cure rates, the increase in treatment abandonment rates, and the increase in MDR-TB rates, being associated with increased mortality from pulmonary tuberculosis during the study period.Keywords: Tuberculosis, pulmonary/epidemiology; Tuberculosis, pulmonary/drug therapy; Tuberculosis, pulmonary/mortality; Interrupted time series analysis; Drug resistance, multiple; Drug compounding.

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Section: Discussionmentioning

confidence: 99%

Evaluation of the impact that the changes in tuberculosis treatment implemented in Brazil in 2009 have had on disease control in the country

2017

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“…A combined dose of HRZE for in vitro treatment was used to mimic the in vivo treatment based on the maximum human blood plasma concentrations (Cmax) of approximately 12.4 µg/ml H, 4.0 µg/ml R, 58 µg/ml Z and 4.3 µg/ml E during chemotherapy respectively 45 . Pleural macrophages were purified from PEMCs as described above and incubated with or without HRZE in a 6-well plate at a concentration of 1 × 10 6 cells/well for 36 hours.…”

Section: Methodsmentioning

confidence: 99%

Antibiotics induce polarization of pleural macrophages to M2-like phenotype in patients with tuberculous pleuritis

Wang

Zhang

Sui

et al. 2017

Sci Rep

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Pleural macrophages play critical roles in pathogenesis of tuberculous pleuritis, but very little is known about their response to anti-tuberculosis antibiotics treatment. Here, we examined whether and how pleural macrophages change in phenotype, transcription and function following antibiotics treatment in patients with tuberculous pleuritis. Results show pro-inflammatory cytokines were down-regulated significantly post antibiotic treatment in the pleural effusions and pleural macrophages up-regulated markers characteristic of M2 macrophages such as CD163 and CD206. Differential expression analysis of transcriptomes from four paired samples before and after treatment identified 230 treatment-specific responsive genes in pleural macrophages. Functional analysis identified interferon-related pathway to be the most responsive genes and further confirmed macrophage polarization to M2-like phenotype. We further demonstrate that expression of a significant fraction of responsive genes was modulated directly by antibiotics in pleural macrophages in vitro. Our results conclude that pleural macrophages polarize from M1-like to M2-like phenotype within a mean of 3.5 days post antibiotics treatment, which is dependent on both pleural cytokine environment and direct modulatory effects of antibiotics. The treatment-specific genes could be used to study the roles of pleural macrophages in the pathogenesis of tuberculous pleuritis and to monitor the response to antibiotics treatment.

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“…Fewer previous studies have been conducted in China comparing the bioequivalence of the anti-TBFDC products available there. [ 11 ] Because there was no certified reference FDC product available in China at the time of this study, we used separate drugs as the reference in this bioequivalence study.…”

Section: Discussionmentioning

confidence: 99%

“…The plasma concentration of RFP was measured using a HPLC-MS/MS method developed in our laboratory. [ 11 ] Briefly, 100 μl of plasma sample was deproteinized with 200 μl of acetonitrile. The mixture was vortexed for 10 s and centrifuged for 10 min at 12,000 g; 2 μl of the supernatant was injected into the chromatographic system.…”

Section: Ethodsmentioning

confidence: 99%

Relative Bioavailability of Rifampicin in Four Chinese Fixed-dose Combinations Compared with Rifampicin in Free Combinations

Zhu¹,

Guo²,

Hao³

et al. 2015

Chinese Medical Journal

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Background:Decreases in the bioavailability of rifampicin (RFP) can lead to the development of drug resistance and treatment failure. Therefore, we investigated the relative bioavailability of RFP from one four-drug fixed-dose combination (FDC; formulation A) and three two-drug FDCs (formulations B, C, and D) used in China, compared with RFP in free combinations of these drugs (reference), in healthy volunteers.Methods:Eighteen and twenty healthy Chinese male volunteers participated in two open-label, randomized two-period crossover (formulations A and C) or one three-period crossover (formulations B and D) study, respectively. The washout period between treatments was 7 days. Bioequivalence was assessed based on 90% confidence intervals, according to two one-sided t-tests. All analyses were done with DAS 3.1.5 (Mathematical Pharmacology Professional Committee of China, Shanghai, China).Results:Mean pharmacokinetic parameter values of RFP obtained for formulations A, B, C, and D products were 11.42 ± 3.41 μg/ml, 7.86 ± 5.78 μg/ml, 13.05 ± 6.80 μg/ml, and 16.18 ± 3.87 μg/ml, respectively, for peak plasma concentration (Cmax), 91.43 ± 30.82 μg·h−1 ·ml−1, 55.49 ± 37.58 μg·h−1 ·ml−1, 96.50 ± 47.24 μg·h−1 ·ml−1, 101.47 ± 33.07 μg·h−1 ·ml−1, respectively, for area under the concentration-time curve (AUC0−24 h).Conclusions:Although the concentrations of RFP for formulations A, C, and D were within the reported acceptable therapeutic range, only formulation A was bioequivalent to the reference product. The three two-drug FDCs (formulations B, C and D) displayed inferior RFP bioavailability compared with the reference (Chinese Clinical Trials registration number: ChiCTR-TTRCC-12002451).

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Oral Bioavailability of Rifampicin, Isoniazid, Ethambutol, and Pyrazinamide in a 4-Drug Fixed-Dose Combination Compared With the Separate Formulations in Healthy Chinese Male Volunteers

Cited by 32 publications

References 4 publications

Evaluation of the impact that the changes in tuberculosis treatment implemented in Brazil in 2009 have had on disease control in the country

Evaluation of the impact that the changes in tuberculosis treatment implemented in Brazil in 2009 have had on disease control in the country

Antibiotics induce polarization of pleural macrophages to M2-like phenotype in patients with tuberculous pleuritis

Relative Bioavailability of Rifampicin in Four Chinese Fixed-dose Combinations Compared with Rifampicin in Free Combinations

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