Optimising pyrazinamide for the treatment of tuberculosis
| Autor: | Marc H Weiner, James E. Posey, Patrick P. J. Phillips, William C. Whitworth, Radojka M. Savic, Erin Bliven-Sizemore, Michael Hoelscher, Rob E. Aarnoutse, Glenn P. Morlock, Kelly E. Dooley, William R. Mac Kenzie, Norbert Heinrich, Martin J. Boeree, Charles A. Peloquin, Nan Zhang, Jason E. Stout |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Tuberculosis medicine.drug_class 030106 microbiology Antibiotics Antitubercular Agents Cmax Pharmacology Article Sputum culture 03 medical and health sciences 0302 clinical medicine All institutes and research themes of the Radboud University Medical Center Pharmacokinetics Isoniazid medicine Culture conversion Humans 030212 general & internal medicine Antibiotics Antitubercular medicine.diagnostic_test business.industry Pyrazinamide medicine.disease lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] Rifampin business Rifampicin medicine.drug |
| Zdroj: | European Respiratory Journal, 58, 1 Eur Respir J European Respiratory Journal, 58 |
| ISSN: | 0903-1936 |
| DOI: | 10.1183/13993003.02013-2020 |
| Popis: | Pyrazinamide is a potent sterilising agent that shortens the treatment duration needed to cure tuberculosis. It is synergistic with novel and existing drugs for tuberculosis. The dose of pyrazinamide that optimises efficacy while remaining safe is uncertain, as is its potential role in shortening treatment duration further.Pharmacokinetic data, sputum culture, and safety laboratory results were compiled from Tuberculosis Trials Consortium (TBTC) studies 27 and 28 and Pan-African Consortium for the Evaluation of Antituberculosis Antibiotics (PanACEA) multi-arm multi-stage tuberculosis (MAMS-TB), multi-centre phase 2 trials in which participants received rifampicin (range 10–35 mg·kg−1), pyrazinamide (range 20–30 mg·kg−1), plus two companion drugs. Pyrazinamide pharmacokinetic–pharmacodynamic (PK–PD) and pharmacokinetic-toxicity analyses were performed.In TBTC studies (n=77), higher pyrazinamide maximum concentration (Cmax) was associated with shorter time to culture conversion (TTCC) and higher probability of 2-month culture conversion (p-valuemax increased and varied by rifampicin area under the curve (p-value4500 mg) or increasing both pyrazinamide and rifampicin would be required to reach targets associated with treatment shortening. Combining all trials, liver toxicity was rare (3.9% with grade 3 or higher liver function tests (LFT)), and no relationship was seen between pyrazinamide Cmax and LFT levels.Pyrazinamide's microbiological efficacy increases with increasing drug concentrations. Optimising pyrazinamide alone, though, is unlikely to be sufficient to allow tuberculosis treatment shortening; rather, rifampicin dose would need to be increased in parallel. |
| Databáze: | OpenAIRE |
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