Abstract
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-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 area under the curve (p-value<0.01). Modelling 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 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.
Abstract
The activity of pyrazinamide, a critical drug for tuberculosis treatment, increases as drug concentrations go up, but optimising this drug alone is unlikely to result in treatment shortening. Rather, rifampicin dosing must increase in parallel. https://bit.ly/2KenbHW
Footnotes
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This study is registered at clinicialtrials.gov (NCT00140309, NCT00144417, NCT01785186). Following de-identification, data may be shared with investigators following an approved use request to the study funders.
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Conflict of interest: N. Zhang has nothing to disclose.
Conflict of interest: R.M. Savic has nothing to disclose.
Conflict of interest: M.J. Boeree has nothing to disclose.
Conflict of interest: C.A. Peloquin has nothing to disclose.
Conflict of interest: M. Weiner has nothing to disclose.
Conflict of interest: N. Heinrich reports grants from EDCTP (EU), during the conduct of the study; personal fees for lectures from AstraZeneca, outside the submitted work.
Conflict of interest: E. Bliven-Sizemore has nothing to disclose.
Conflict of interest: P.P.J. Phillips reports grants from EDCTP, during the conduct of the study.
Conflict of interest: M. Hoelscher has nothing to disclose.
Conflict of interest: W. Whitworth has nothing to disclose.
Conflict of interest: G. Morlock has nothing to disclose.
Conflict of interest: J. Posey has nothing to disclose.
Conflict of interest: J.E. Stout has nothing to disclose.
Conflict of interest: W. Mac Kenzie has nothing to disclose.
Conflict of interest: R. Aarnoutse has nothing to disclose.
Conflict of interest: K.E. Dooley has nothing to disclose.
Support statement: TBTC Studies S27 and S28 were supported by the Centers for Disease Control and Prevention, Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, and the Global Alliance for Tuberculosis Drug Development. Bayer donated drugs for S27 and S28. PanACEA MAMS-TB was funded by the European and Developing Countries Clinical Trials partnership (EDCTP Project-ID: IP.2007.32011.011), the German Ministry for Education and Research (BMBF, grant 01KA0901), and the Medical Research Council UK (MRC). The EDCTP, BMBF and MRC were not involved in the study conduct, data analysis and writing of the report. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received May 29, 2020.
- Accepted December 11, 2020.
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