ArticleAntimicrobial agents and chemotherapy2012
Feasibility of a fixed-dose regimen of pyrazinamide and its impact on systemic drug exposure and liver safety in patients with tuberculosis.
Article in Antimicrobial agents and chemotherapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 26 citations in OpenAlex.
- Optimising pyrazinamide for the treatment of tuberculosis.The European respiratory journal · 2021Trial
- Phase 2C clinical trial of novel short-course regimens for the treatment of pulmonary tuberculosis: TBTC study 38/CRUSH-TB design.Contemporary clinical trials · 2025Article
- Optimizing β-lactam-containing antibiotic combination therapy for the treatment of Buruli ulcer.British journal of clinical pharmacology · 2025Article
- A Balancing Act: Finding the Right Dose of Pyrazinamide to Treat Tuberculosis.American journal of respiratory and critical care medicine · 2024Article
- Article
- The impact of inclusion, dose and duration of pyrazinamide (PZA) on efficacy and safety outcomes in tuberculosis: systematic review and meta-analysis protocol.Systematic reviews · 2019Article
- How long will treatment guidelines for TB continue to overlook variability in drug exposure?The Journal of antimicrobial chemotherapy · 2019Article
- Mimicking in-vivo exposures to drug combinations in-vitro: anti-tuberculosis drugs in lung lesions and the hollow fiber model of infection.Scientific reports · 2019Article
- Efficacy Versus Hepatotoxicity of High-dose Rifampin, Pyrazinamide, and Moxifloxacin to Shorten Tuberculosis Therapy Duration: There Is Still Fight in the Old Warriors Yet!Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2018Article
- Toxicity associated with tuberculosis chemotherapy in the REMoxTB study.BMC infectious diseases · 2018Article
- Pharmacokinetics of Pyrazinamide and Optimal Dosing Regimens for Drug-Sensitive and -Resistant Tuberculosis.Antimicrobial agents and chemotherapy · 2017Article
- Liver Fatty Acid Binding Protein Deficiency Provokes Oxidative Stress, Inflammation, and Apoptosis-Mediated Hepatotoxicity Induced by Pyrazinamide in Zebrafish Larvae.Antimicrobial agents and chemotherapy · 2016Article
- Pharmacokinetic Evaluation of Sulfamethoxazole at 800 Milligrams Once Daily in the Treatment of Tuberculosis.Antimicrobial agents and chemotherapy · 2016Article
- Generating Virtual Patients by Multivariate and Discrete Re-Sampling Techniques.Pharmaceutical research · 2015Article
- Comparative study of the effects of antituberculosis drugs and antiretroviral drugs on cytochrome P450 3A4 and P-glycoprotein.Antimicrobial agents and chemotherapy · 2014Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Historically, dosing regimens for the treatment of tuberculosis (TB) have been proposed in an empirical manner. Dose selection has often been the result of efficacy trials in which drugs were administered regardless of the magnitude of the effect of demographic factors on drug disposition. This has created challenges for the prescription of fixed-dose combinations with novel therapeutic agents. The objectives of this investigation were to evaluate the impact of body weight on the overall systemic exposure to pyrazinamide (PZA) and to assess whether the use of one fixed dose, without adjustment according to weight, would ensure target exposure and safety requirements across the overall patient population. Using a population pharmacokinetic model, simulation scenarios were explored based on population demographics from clinical trials in TB patients and on historical hepatotoxicity data. The systemic drug exposure (area under the concentration-time curve [AUC]), peak concentrations (the maximum concentration of drug in serum [C(max)]), the time above the MIC (t > MIC), and the risk of hepatotoxicity were evaluated for the current weight-banded regimen and compared to fixed doses under the assumption that pharmacokinetic differences are the primary drivers of toxicity. Evaluation of the standard weight banding reveals that more than 50% of subjects in the weight range of 45 to 55 kg remain below the proposed target exposure to PZA. In contrast, the use of a fixed 1,500-mg dose resulted in a lower proportion of subjects under the target value, with a 0.2% average overall increase in the risk of hepatotoxicity. Our results strongly support the use of a fixed-dose regimen for PZA in coformulation or combination with novel therapeutic agents.
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