RT Journal Article
SR Electronic
T1 Optimising pyrazinamide for the treatment of tuberculosis
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 2002013
DO 10.1183/13993003.02013-2020
A1 Nan Zhang
A1 Radojka M. Savic
A1 Martin J. Boeree
A1 Charles Peloquin
A1 Marc Weiner
A1 Norbert Heinrich
A1 Erin Bliven-Sizemore
A1 Patrick PJ Phillips
A1 Michael Hoelscher
A1 William Whitworth
A1 Glenn Morlock
A1 James Posey
A1 Jason E. Stout
A1 William Mac Kenzie
A1 Robert Aarnoutse
A1 Kelly E. Dooley
A1 the Tuberculosis Trials Consortium (TBTC) and Pan African Consortium for the Evaluation of Antituberculosis Antibiotics (PanACEA) Networks
YR 2021
UL http://erj.ersjournals.com/content/early/2020/12/17/13993003.02013-2020.abstract
AB 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 TBTC Studies 27 and 28 and PanACEA MAMS-TB, multi-center 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 PK-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 two-month culture conversion (p-value<0.001). Parametric survival analyses showed that relationships varied geographically, with steeper PK-PD relationships seen among non-African than African participants. In PanACEA MAMS-TB (n=363), TTCC decreased as pyrazinamide Cmax increased and varied by rifampicin Cmax (p-value<0.01). Modeling and simulation suggested that very high doses of pyrazinamide (>4500 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 microbiologic 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.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Zhang has nothing to disclose.Conflict of interest: Dr. Savic has nothing to disclose.Conflict of interest: Dr. Boeree has nothing to disclose.Conflict of interest: Dr. Peloquin has nothing to disclose.Conflict of interest: Dr. Weiner has nothing to disclose.Conflict of interest: Dr. Heinrich reports grants from EDCTP (EU), during the conduct of the study; personal fees from AstraZeneca, outside the submitted work;.Conflict of interest: Ms. Sizemore has nothing to disclose.Conflict of interest: Dr. Phillips reports grants from EDCTP, during the conduct of the study;.Conflict of interest: Dr. Hoelscher has nothing to disclose.Conflict of interest: Dr. Whitworth has nothing to disclose.Conflict of interest: Dr. Morlock has nothing to disclose.Conflict of interest: Dr. Posey has nothing to disclose.Conflict of interest: Dr. Stout has nothing to disclose.Conflict of interest: Dr. Mac Kenzie has nothing to disclose.Conflict of interest: Dr. Aarnoutse has nothing to disclose.Conflict of interest: Dr. Dooley has nothing to disclose.