A Novel Mechanism Underlies the Hepatotoxicity of Pyrazinamide

Shih, Tiffany Ting-Fang; Pai, Chien Yi; Yang, Ping; Chang, Wen; Wang, Ning Chi; Hu, Oliver Yoa Pu

doi:10.1128/aac.01866-12

Cited by 86 publications

(69 citation statements)

References 23 publications

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“…The current recommended weight-adjusted daily dose of pyrazinamide for treatment of drug-susceptible TB is approximately 25 (range, 20 to 30) mg/kg of body weight (14), while that for treatment of MDR-TB is about 35 (range, 30 to 40) mg/kg (15). Doses higher than those currently recommended may result in high levels of 5-hydroxypyrazinoic acid, which is responsible for pyrazinamide induced hepatotoxicity (16). On the other hand, there exist discrepancies in exposure between the weight bands; patients in the lower weight bands achieve lower drug exposures (17,18).…”

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confidence: 99%

Pharmacokinetics of Pyrazinamide and Optimal Dosing Regimens for Drug-Sensitive and -Resistant Tuberculosis

Chirehwa

McIlleron

Rustomjee

et al. 2017

Antimicrob Agents Chemother

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Pyrazinamide is used in the treatment of tuberculosis (TB) because its sterilizing effect against tubercle bacilli allows the shortening of treatment. It is part of standard treatment for drug-susceptible and drug-resistant TB, and it is being considered as a companion drug in novel regimens. The aim of this analysis was to characterize factors contributing to the variability in exposure and to evaluate drug exposures using alternative doses, thus providing evidence to support revised dosing recommendations for drug-susceptible and multidrug-resistant tuberculosis (MDR-TB). Pyrazinamide pharmacokinetic (PK) data from 61 HIV/TB-coinfected patients in South Africa were used in the analysis. The patients were administered weight-adjusted doses of pyrazinamide, rifampin, isoniazid, and ethambutol in fixed-dose combination tablets according to WHO guidelines and underwent intensive PK sampling on days 1, 8, 15, and 29. The data were interpreted using nonlinear mixed-effects modeling. PK profiles were best described using a one-compartment model with first-order elimination. Allometric scaling was applied to disposition parameters using fat-free mass. Clearance increased by 14% from the 1st day to the 29th day of treatment. More than 50% of patients with weight less than 55 kg achieved lower pyrazinamide exposures at steady state than the targeted area under the concentration-time curve from 0 to 24 h of 363 mg · h/liter. Among patients with drug-susceptible TB, adding 400 mg to the dose for those weighing 30 to 54 kg improved exposure. Average pyrazinamide exposure in different weight bands among patients with MDR-TB could be matched by administering 1,500 mg, 1,750 mg, and 2,000 mg to patients in the 33-to 50-kg, 51-to 70-kg, and greater than 70-kg weight bands, respectively.KEYWORDS NONMEM, population pharmacokinetics, HIV/TB coinfection, fat-free mass, AUC, weight band dosing P yrazinamide is a prodrug converted to its active form, pyrazinoic acid, by hepatic microsomal deamidase (1) and is active against dormant and semidormant Mycobacterium tuberculosis bacilli, especially in acidic environments (2, 3). It is currently part of a four-drug fixed-dose combination (FDC), which includes isoniazid, ethambutol, and rifampin, an inducer of a number of cytochrome P450 enzymes via the pregnane X receptor (PXR) (4). Pyrazinamide is currently being considered as a companion drug in novel tuberculosis (TB) treatment regimens (5-7), including for multidrug-resistant tuberculosis (MDR-TB).Interest in the drug derives from its potent sterilizing activity, which confers the ability to shorten treatment duration. Pyrazinamide exposures have been correlated with favorable treatment outcomes in patients on standard doses (5, 8-13). A pyrazi-

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confidence: 99%

Pharmacokinetics of Pyrazinamide and Optimal Dosing Regimens for Drug-Sensitive and -Resistant Tuberculosis

Chirehwa

McIlleron

Rustomjee

et al. 2017

Antimicrob Agents Chemother

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“…A key enzyme, N-acetyltransferase 2 (NAT2), is involved in the metabolism of INH to acetyl INH, as well as in the conversion of acetyl hydrazine to non-toxic diacetyl hydrazine [17]. Patients who possess NAT2*6/6 and NAT2*6/7 genotypes, which are associated with slow acetylation, have a higher risk of INH-induced hepatotoxicity [7]. Furthermore, INH is a cytochrome P450 protein (CYP) 2E1 inhibitor; the CYP2E1 C/D and C/C genotypes exhibit a higher frequency in ATDH patients [19].…”

Section: Discussionmentioning

confidence: 99%

“…Although anti-TB drugs have been used for decades worldwide, the mechanism of ATDH is not fully understood. Apart from the hepatic cell injury that is caused by anti-TB drugs via drug-metabolite adduct formation, the chain reaction of reactive metabolite formation, excessive reactive oxygen species generation, lipid peroxidation, mitochondrial respiratory chain suppression, adenosine triphosphate depletion, hepatic cells apoptosis or necrosis are involved in ATDH [7,10,17]. The first-line anti-TB drugs, INH, RIF, and PZA are common drugs that are related to liver injury because they are metabolized in the liver [18].…”

Section: Discussionmentioning

confidence: 99%

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Is the Prophylactic Use of Hepatoprotectants Necessary in Anti-Tuberculosis Treatment?

Zhang²,

Chen³

et al. 2017

Chemotherapy

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Background: Liver injury is one of the serious side effects of anti-tuberculosis (TB) drugs. It is controversial whether hepatoprotectant prophylaxis is efficient and safe in anti-TB treatment, so we aimed to assess the efficacy and safety of hepatoprotectant prophylaxis in patients who had received anti-TB treatment. Methods: PubMed, the Cochrane library, Embase, Ovid, Springer link, Wiley, Elsevier, Web of Science, and the Karger Online Journal were systematically searched prior to April 2016 for articles related to hepatoprotectant prophylaxis in the treatment of TB. A meta-analysis was conducted to estimate the effect of hepatoprotective agents on liver function and adverse events (AEs) in patients who had received anti-TB drugs. The primary outcomes were changes in alanine transaminase (ALT) and aspartate transaminase (AST) levels. The other outcomes were drug-induced liver injury (DILI) and AEs. Results: In our review, 6 trials that involved 1,227 patients were included. Our analysis indicated that hepatoprotective agents exerted protective effects on liver function in patients who had received anti-TB drugs (weighted mean difference, WMD = -7.81, 95% CI [-12.26, -3.37], p = 0.0006 [ALT]; WMD = -7.07, 95% CI [-11.43, -2.72], p = 0.001 [AST]) in any age group. However, in the subgroup analysis of treatment duration, the use of hepatoprotective agents was not associated with significant changes in ALT and AST levels after 2 weeks of treatment and exhibited a positive effect on liver function after 4 weeks of treatment. Moreover, the use of hepatoprotectants significantly decreased the number of DILI cases (risk ratio, RR 0.50, 95% CI [0.34-0.73], p = 0.0004). However, the use of hepatoprotectants led to similar AEs in the control groups (RR 1.07, 95% CI [0.82-1.39], p = 0.62). Conclusions: The use of hepatoprotective drugs may prevent liver injury in patients who are receiving anti-TB drugs without any significant AEs 4 weeks after the initiation of hepatoprotective medication.

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“…TB is a highly prevalent chronic devastating disease caused by Mycobacterium tuberculosis. This bacteria is a sedentary, obligate aerobic, acid fast facultative intracellular rod-shaped bacterium, with long generation time and preference to localize in macrophage and typically affects the lungs (pulmonary TB) but can affect other sites as well as extra pulmonary TB (2,3). The most common method to detect TB is sputum smear microscopy.…”

Section: Introductionmentioning

confidence: 99%

Hematological and liver toxicity of anti-tuberculosis drugs

Mirlohi¹,

Ekrami²,

Shirali³

et al. 2016

Electron physician

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Introduction: Tuberculosis (TB) is a major global health problem, and anti-tuberculosis drugs can cause severe adverse reactions. The aim of this study was to determine hematological and biochemical changes and associated risk factors in smear positive pulmonary tuberculosis patients undergoing treatment with standard protocols. Methods: In a descriptive study, a total of 40 tuberculosis patients aged between 15-60 years were collected from hospitals in Khuzestan Province (Iran) from March 2013 to March 2014. The patients were treated with drugs (isoniazid, rifampicin, ethambutol, and pyrazinamide) during the initial two months, followed by isoniazid and rifampicin for the next four to six months. Activities of liver enzymes (ALT, AST, and ALP) and hematological parameters were recorded before and after treatment. Data were analyzed using paired samples t-test and Wilcoxon test by SPSS 16. Results: After using drug treatments, hematological parameters (RBC, Hb, HCT, MCV, MCH, and MCHC), except platelet count, were changed significantly (p ≤ 0.001). Liver enzyme activities (ALT, AST, and ALP) were decreased significantly (p ≤ 0.001) after treatment. Conclusion: In this study, changes of hematological and biochemical parameters have been observed in patients with pulmonary tuberculosis. It can be concluded that the anti-tuberculosis treatment is associated with changes of hematological parameters and liver enzymes.

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A Novel Mechanism Underlies the Hepatotoxicity of Pyrazinamide

Cited by 86 publications

References 23 publications

Pharmacokinetics of Pyrazinamide and Optimal Dosing Regimens for Drug-Sensitive and -Resistant Tuberculosis

Pharmacokinetics of Pyrazinamide and Optimal Dosing Regimens for Drug-Sensitive and -Resistant Tuberculosis

Is the Prophylactic Use of Hepatoprotectants Necessary in Anti-Tuberculosis Treatment?

Hematological and liver toxicity of anti-tuberculosis drugs

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