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.