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 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.

Safety and pharmacokinetics-pharmacodynamics of a shorter tuberculosis treatment with high-dose pyrazinamide and rifampicin: a study protocol of a phase II clinical trial (HighShort-RP)

“…In a PK-PD modelling study published just after our study opened for recruitment, the relationship between pyrazinamide exposures and efficacy or hepatotoxicity was assessed on pooled retrospective data from three clinical interventional trials conducted by the Tuberculosis Trials Consortium and Pan African Consortium for the Evaluation of Antituberculosis Antibiotics Networks. 25 Simulations identified two potentially treatment-shortening strategies restricted to currently used first-line drugs whereof one was to optimise drug exposure of rifampicin and pyrazinamide in parallel. The authors stated that whether or not an enhanced multidrug regimen based on high-dose rifampicin (eg, ≥35 mg/kg) and higherdose pyrazinamide (eg, 30-40 mg/kg) will be sufficient to significantly reduce the length of TB treatment must be explored prospectively, with attention to safety and tolerability.…”

“…23 24 In a large PK-PD study evaluating patient-level data from three phase II clinical trials with pulmonary TB patients where the majority had cavitary disease, participants received rifampicin (range 10-35 mg/kg), pyrazinamide (range 20-30 mg/kg) and two companion drugs. 25 The results showed that pyrazinamide's induction of culture negativity increased with augmented drug exposure. Hepatotoxicity was rare and not associated with pyrazinamide exposure.…”

“…Furthermore, PK modelling suggested that a massive dose of pyrazinamide (>4500 mg) or increasing both pyrazinamide and rifampicin doses would be required to reach microbiological targets associated with treatmentshortening such as 90%-95% culture conversion rate by 2 months of treatment. 25 Rifampicin doses of at least three times the standard dose combined with isoniazid, pyrazinamide and ethambutol was safely administered to 63 patients with pulmonary TB for 12 weeks. 11 Rifampicin 40 mg/kg was recently identified as the highest tolerated dose with dose limiting factors reported as gastrointestinal disorders, pruritus, hyperbilirubinaemia and jaundice.…”

“…47 Recently, a patient-level data analysis where patients received rifampicin (range 10-35 mg/kg), pyrazinamide (range 20-30 mg/kg), plus two companion drugs, found liver toxicity to be rare (3.9% with grade 3 or higher liver Open access function tests, LFT), and no relationship was observed between pyrazinamide C max and LFT levels. 25 Furthermore, currently used doses of 30-40 mg/kg pyrazinamide daily as part of MDR-TB treatment are well tolerated. 54 In summary, we consider it safe for patients to participate in our clinical trial and study participants will be closely monitored regarding potential side effects including weekly measurement of LFT during the first 8 weeks when high-dose pyrazinamide and rifampicin are combined.…”

Performance of Wayne assay for detection of pyrazinamide resistance in Mycobacterium tuberculosis: a meta-analysis study

“…The increasing rate of multidrug-resistant TB (MDR-TB) is one of the most critical threats to TB control [ 2 ]. Pyrazinamide (PZA) is an essential anti-TB drug that is frequently used in both first- and second-line treatment regimens [ [3] , [4] , [5] , [6] ]. Although PZA is a cornerstone in the treatment of TB, its drug susceptibility testing (DST) is not routinely performed due to technical limitations (i.e., inoculum size, long turnaround time, an acidic culture medium, etc.)…”