Optimising pyrazinamide for the treatment of tuberculosis

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.

Trial registration: ClinicalTrials.gov NCT00140309 NCT00144417 NCT01785186.

Conflict of interest statement

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.

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Figures

Figure 1.

Visual predictive checks of the PK/outcome Weibull survival models for TBTC S27/28 (A) and PanANCEA MAMS trials stratified by covariates identified in the survival model (B).

Figure 1.

Visual predictive checks of the PK/outcome Weibull survival models for TBTC S27/28 (A) and PanANCEA MAMS trials stratified by covariates identified in the survival model (B).

Figure 2.

Among participants taking combination treatment including pyrazinamide and standard-dose rifampicin in TBTC Studies 27 and 28, the relationship between maximum drug concentration (mcg/mL) and proportion with culture conversion to negative by 2 months of treatment. The median Cmax with drug doses of 1000mg, 1500mg, and 2000mg are shown in the vertical dash lines, and the observed range of Cmax values is contained within the vertical grey lines. In Panel a, the grey ribbon shows the 90% confidence interval of the proportion with culture conversion to negative with the black line as the median. In Panel b, the relationship between Cmax and two-month culture conversion is shown for African vs. non-African participants.

Figure 3.

Simulated relationship between culture conversion on liquid medium by 2 months of treatment with maximum concentrations (Cmax) of pyrazinamide and area under the curve (AUC0-24hr) of rifampicin from PanACEA MAMS trial. Black dots are Cmax values of pyrazinamide and rifampicin obtained by population PK models. Notes: for patients whose PK concentrations were not measured, pyrazinamide Cmax values were imputed using the population PK model and rifampicin AUC values were imputed using geometric mean values of the regimen taken.

Figure 4.

(A) Distribution and regression of individual maximal AST (left) and maximal total bilirubin (right) versus observed Cmax of pyrazinamide in TBTC 27 and 28 trials. (B) Distribution and regression of individual maximal ALT (left), individual maximal AST (middle), and individual total bilirubin (right) versus of pyrazinamide Cmax in PanANCEA MAMS trial.

Figure 4.

(A) Distribution and regression of individual maximal AST (left) and maximal total bilirubin (right) versus observed Cmax of pyrazinamide in TBTC 27 and 28 trials. (B) Distribution and regression of individual maximal ALT (left), individual maximal AST (middle), and individual total bilirubin (right) versus of pyrazinamide Cmax in PanANCEA MAMS trial.