ArticleAntimicrobial agents and chemotherapy2011
PA-824 exhibits time-dependent activity in a murine model of tuberculosis.
Article in Antimicrobial agents and chemotherapy, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 85 citations in OpenAlex.
- Pharmacokinetics, bactericidal activity and toxicity of short oral regimens for rifampicin-resistant tuberculosis treatment.Nature communications · 2026Trial
- Population pharmacokinetics and target attainment of pretomanid in rifampicin-resistant tuberculosis patients.Scientific reports · 2026Trial
- Assessing Pretomanid for Tuberculosis (APT), a Randomized Phase 2 Trial of Pretomanid-Containing Regimens for Drug-Sensitive Tuberculosis: 12-Week Results.American journal of respiratory and critical care medicine · 2023Trial
- Characterizing Absorption Properties of Dispersible Pretomanid Tablets Using Population Pharmacokinetic Modelling.Clinical pharmacokinetics · 2022Trial
- Pretomanid dose selection for pulmonary tuberculosis: An application of multi-objective optimization to dosage regimen design.CPT: pharmacometrics & systems pharmacology · 2021Trial
- Pretomanid Pharmacokinetics in the Presence of Rifamycins: Interim Results from a Randomized Trial among Patients with Tuberculosis.Antimicrobial agents and chemotherapy · 2021Trial
- Phase I safety, pharmacokinetics, and pharmacogenetics study of the antituberculosis drug PA-824 with concomitant lopinavir-ritonavir, efavirenz, or rifampin.Antimicrobial agents and chemotherapy · 2014Trial
- Phase II dose-ranging trial of the early bactericidal activity of PA-824.Antimicrobial agents and chemotherapy · 2012Trial
- Cerebrospinal Fluid Concentrations of Bedaquiline, Pretomanid, and Linezolid During Curative Treatment of Fluoroquinolone-Resistant Pre-Extensively Drug-Resistant Tuberculous Meningitis.Open forum infectious diseases · 2026Article
- Bedaquiline, Pretomanid, Linezolid, and Moxifloxacin: Mechanisms of Action, Drug Interactions, Adverse Effects and Use in Special Situations.Microorganisms · 2026Review
- Article
- A modeling-based framework to evaluate forgiveness of tuberculosis treatment in a BALB/c relapsing mouse model.Antimicrobial agents and chemotherapy · 2026Article
- Pharmacology of emerging drugs for the treatment of multi-drug resistant tuberculosis.Journal of clinical tuberculosis and other mycobacterial diseases · 2024Review
- Dynamic PET reveals compartmentalized brain and lung tissue antibiotic exposures of tuberculosis drugs.Nature communications · 2024Observational
- Role of therapeutic drug monitoring in the treatment of multi-drug resistant tuberculosis.Journal of clinical tuberculosis and other mycobacterial diseases · 2024Article
- Dynamic PET Reveals Compartmentalized Brain and Lung Tissue Antibiotic Exposures.Research square · 2024Article
- Acceleration of infectious disease drug discovery and development using a humanized model of drug metabolism.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Predictions of Bedaquiline and Pretomanid Target Attainment in Lung Lesions of Tuberculosis Patients using Translational Minimal Physiologically Based Pharmacokinetic Modeling.Clinical pharmacokinetics · 2023Article
- DynamicNature communications · 2022Article
- Ancient and recent differences in the intrinsic susceptibility of Mycobacterium tuberculosis complex to pretomanid.The Journal of antimicrobial chemotherapy · 2022Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
PA-824 is one of two nitroimidazoles in phase II clinical trials to treat tuberculosis. In mice, it has dose-dependent early bactericidal and sterilizing activity. In humans with tuberculosis, PA-824 demonstrated early bactericidal activity (EBA) at doses ranging from 200 to 1,200 mg per day, but no dose-response effect was observed. To better understand the relationship between drug exposure and effect, we performed a dose fractionation study in mice. Dose-ranging pharmacokinetic data were used to simulate drug exposure profiles. Beginning 2 weeks after aerosol infection with Mycobacterium tuberculosis, total PA-824 doses from 144 to 4,608 mg/kg were administered as 3, 4, 8, 12, 24, or 48 divided doses over 24 days. Lung CFU counts after treatment were strongly correlated with the free drug T(>MIC) (R(2) = 0.87) and correlated with the free drug AUC/MIC (R(2) = 0.60), but not with the free drug C(max)/MIC (R(2) = 0.17), where T(>MIC) is the cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions and AUC is the area under the concentration-time curve. When the data set was limited to regimens with dosing intervals of ≤72 h, both the T(>MIC) and the AUC/MIC values fit the data well. Free drug T(>MIC) of 22, 48, and 77% were associated with bacteriostasis, a 1-log kill, and a 1.59-log kill (or 80% of the maximum observed effect), respectively. Human pharmacodynamic simulations based on phase I data predict 200 mg/day produces free drug T(>MIC) values near the target for maximal observed bactericidal effect. The results support the recently demonstrated an EBA of 200 mg/day and the lack of a dose-response between 200 and 1,200 mg/day. T(>MIC), in conjunction with AUC/MIC, is the parameter on which dose optimization of PA-824 should be based.
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