Cytokines and acute-phase serum proteins as markers of inflammatory regression during pulmonary tuberculosis treatment

Peresi, Eliana

doi:10.1590/s1678-91992008000100019

Cited by 23 publications

(36 citation statements)

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“…Differences could be caused by altered levels of plasma proteins (BDQ is Ͼ99.99% bound [11], and the concentration of plasma albumin is decreased in patients with TB [35] or TB/HIV coinfections [36]), altered bioavailability (37), or malnutrition. BDQ and M2 exposures were generally lower in patients with MDR-TB than would be expected based on data from healthy volunteers, and differences in bedaquiline CL and bioavailability have been shown (11,24).…”

Section: Discussionmentioning

confidence: 99%

Impact of Lopinavir-Ritonavir or Nevirapine on Bedaquiline Exposures and Potential Implications for Patients with Tuberculosis-HIV Coinfection

Svensson

Dooley

Karlsson

2014

Antimicrob Agents Chemother

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Early initiation of antiretroviral therapy (ART) during TB therapy substantially reduces TB-related morbidity and mortality rates for coinfected patients (2, 3), and the World Health Organization recommends that ART be started as soon as possible but within 8 weeks after the initiation of TB therapy (4). Simultaneously, the global emergence and increased dissemination of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB have increased the need for novel anti-TB drugs with new mechanisms of action. Data from Eastern Europe indicate that multidrug resistance is approximately twice as common among patients with TB who have HIV, compared with patients without HIV (5), and a South African study found that 100% of patients with XDR-TB who were tested had HIV infections (6). Ensuring access to novel anti-TB compounds and determining safe and efficacious doses for coinfected patients must be priorities (7).The diarylquinoline bedaquiline (BDQ) (previously called TMC207) was recently approved for the treatment of MDR-TB and XDR-TB by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency. The mechanism of action is novel and involves the inhibition of mycobacterial ATP synthase, leading to disrupted energy metabolism (8, 9). Phase II trials showed that BDQ significantly decreased the time to sputum culture conversion and increased the proportion of patients with negative culture results after 6 months of treatment, when added to a regimen of other anti-TB drugs (10,11). This treatment benefit was sustained at the end of the 120-week trial (12). The exposure-response relationship for BDQ is poorly characterized, but a recent study of early bactericidal activity detected a linear increase in bactericidal activity with increasing doses over 14 days of treatment (13). The main safety issue for BDQ is moderate QT prolongation; in addition, an unexplained increase in late deaths, compared to the placebo group, was observed in one phase II study in which all patients also received standard MDR-TB treatment, which resulted in a black-box warning in the U.S. label (12,14). In general, however, BDQ is better tolerated than other second-line TB drugs, the majority of which produce clinically significant and often treatment-limiting side effects (15). The current standard dosing regimen for BDQ is 2 weeks of 400 mg given daily, followed by 22 weeks of 200 mg administered three times per week. BDQ is extensively distributed to the tissues and has a multiphasic elimination pattern with a long terminal half-life (4 to 5 months) (16,17). It is mainly metabolized by the cytochrome P450 (CYP) enzyme CYP3A4 to a N-monodesmethyl metabolite, M2 (38). The activity of M2 against Mycobacterium tuberculosis is 3-to 6-fold weaker than the activity of BDQ, and there is concern that the metabolite may have a higher risk of toxicity (39). M2, though, circulates at much lower concentrations than the parent drug in humans. M2 is further primarily demethylated to the M3 metabolite, likely also by CYP3A4 (11,18).Ne...

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Section: Discussionmentioning

confidence: 99%

Impact of Lopinavir-Ritonavir or Nevirapine on Bedaquiline Exposures and Potential Implications for Patients with Tuberculosis-HIV Coinfection

Svensson

Dooley

Karlsson

2014

Antimicrob Agents Chemother

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“…BDQ, though, is extensively bound to plasma proteins, Ͼ99.9% (16), and it is known that levels of certain proteins are altered in patients with active TB. In general, the albumin level is decreased, while the level of ␣1-acid glycoprotein (AAG) is increased (34). It has also been reported that albumin levels are even further decreased in TB patients coinfected with HIV (35).…”

Section: Discussionmentioning

confidence: 99%

Model-Based Estimates of the Effects of Efavirenz on Bedaquiline Pharmacokinetics and Suggested Dose Adjustments for Patients Coinfected with HIV and Tuberculosis

Svensson

Aweeka

Park

et al. 2013

Antimicrob Agents Chemother

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d Safe, effective concomitant treatment regimens for tuberculosis (TB) and HIV infection are urgently needed. Bedaquiline (BDQ) is a promising new anti-TB drug, and efavirenz (EFV) is a commonly used antiretroviral. Due to EFV's induction of cytochrome P450 3A4, the metabolic enzyme responsible for BDQ biotransformation, the drugs are expected to interact. Based on data from a phase I, single-dose pharmacokinetic study, a nonlinear mixed-effects model characterizing BDQ pharmacokinetics and interaction with multiple-dose EFV was developed. BDQ pharmacokinetics were best described by a 3-compartment disposition model with absorption through a dynamic transit compartment model. Metabolites M2 and M3 were described by 2-compartment models with clearance of BDQ and M2, respectively, as input. Impact of induction was described as an instantaneous change in clearance 1 week after initialization of EFV treatment and estimated for all compounds. The model predicts average steady-state concentrations of BDQ and M2 to be reduced by 52% (relative standard error [RSE], 3.7%) with chronic coadministration. A range of models with alternative structural assumptions regarding onset of induction effect and fraction metabolized resulted in similar estimates of the typical reduction and did not offer a markedly better fit to data. Simulations to investigate alternative regimens mitigating the estimated interaction effect were performed. The results suggest that simple adjustments of the standard regimen during EFV coadministration can prevent reduced exposure to BDQ without increasing exposures to M2. However, exposure to M3 would increase. Evaluation in clinical trials of adjusted regimens is necessary to ensure appropriate dosing for HIV-infected TB patients on an EFV-based regimen. C oinfection with tuberculosis (TB) and HIV is common. Of 8.7 million patients with incident TB in 2011, about 13% were HIV infected (1). TB is a leading cause of death among HIVinfected individuals in low-and middle-income countries (2). Safe, effective concomitant treatment regimens for the two infections are urgently needed given that concurrent treatment, rather than sequential treatment, is now the standard of care (3). Drugdrug interactions (DDIs) and overlapping toxicities, however, complicate HIV-TB cotreatment (4). Bedaquiline (BDQ), formerly known as TMC207, is a diarylquinoline just recently approved by the Food and Drug Administration for treatment of multidrug-resistant TB (MDR-TB). This makes bedaquiline the first new licensed drug for TB with a novel mechanism of action in decades. The recommended dosing regimen is 2 weeks of 400 mg once daily (QD) followed by 22 weeks of 200 mg three times per week. BDQ targets bacterial ATP synthase and disrupts energy metabolism (5, 6). BDQ has demonstrated antimycobacterial activity in vitro (7,8), in animal models (9-11), and among patients with TB (12-14). It has been suggested that BDQ could also improve and simplify treatment of drug-sensitive TB by shortening the treatment duration required fo...

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“…It is known that the activation of the immune system mediates the systemic inflammation seen in the disease [4][5][6]. An increase in C-reactive protein (CRP), due to increased hepatic synthesis of acute phase proteins, and an increase in ESR follow the inflammatory process and hence these parameters are used in the diagnosis and follow-up of patients [7]. Studies have proved that CRP can serve as a sensitive indicator of activity of tuberculosis and the return to normal values of initially elevated CRP levels may indicate a good therapeutic response [8].…”

Section: Introductionmentioning

confidence: 99%

Assessment of Hematological Parameters in Pulmonary Tuberculosis Patients

et al. 2015

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The aim of the study was the assessment of hematological parameters in pulmonary tuberculosis patients. Forty patients diagnosed with tuberculosis were recruited from the Institute of Thoracic Medicine on the basis of history, clinical examination, chest radiography, sputum examination and related laboratory parameters and were compared with age and sex matched healthy volunteers (n = 40). Hematological parameters and CRP in tuberculosis patients were determined. The mean values for serum hemoglobin level, RBC count and platelet count in PTB was found to be less (p \ 0.001). Erythrocyte sedimentation rate (ESR), plasma C-reactive protein, WBC count in PTB subjects was increased (p \ 0.001 for ESR & CRP, p \ 0.05 for WBCs) and all were statistically significant. This study demonstrated that serum hemoglobin level, RBC count and platelet count was decreased in tuberculosis patients whereas ESR, CRP and WBC count was increased when compared with healthy controls.

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Cytokines and acute-phase serum proteins as markers of inflammatory regression during pulmonary tuberculosis treatment

Cited by 23 publications

References 0 publications

Impact of Lopinavir-Ritonavir or Nevirapine on Bedaquiline Exposures and Potential Implications for Patients with Tuberculosis-HIV Coinfection

Impact of Lopinavir-Ritonavir or Nevirapine on Bedaquiline Exposures and Potential Implications for Patients with Tuberculosis-HIV Coinfection

Model-Based Estimates of the Effects of Efavirenz on Bedaquiline Pharmacokinetics and Suggested Dose Adjustments for Patients Coinfected with HIV and Tuberculosis

Assessment of Hematological Parameters in Pulmonary Tuberculosis Patients

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