Is there a need to optimise pyrazinamide doses in patients with tuberculosis?: A Systematic Review.

Pyrazinamide is a first-line tuberculosis drug with potent sterilizing activity. Variability in drug exposure may potentially translate into suboptimal treatment responses. This systematic review aimed to evaluate the concentration-effect relationship. The study was conducted according to PRISMA guidelines. In-vitro and in-vivo studies had to contain information on the infection model, pyrazinamide dose and concentration and microbiological outcome. Human studies had to present information on the pyrazinamide dose, measures of drug exposure and maximum concentration, microbiological response parameter or overall treatment outcome. A total of 34 studies were assessed including in-vitro (n=2), in-vivo (n=3), and clinical studies (n=29). Intra-cellular and extracellular models demonstrated a direct correlation between a pyrazinamide dose of 15 - 50 mg/kg/day and reduction in bacterial count between 0.50 - 27.7 log10 CFU/mL. Consistent with this, higher pyrazinamide doses (>150 mg/kg) were associated with a greater reduction in bacterial burden in BALB/c mice models. Human pharmacokinetic studies displayed a linear positive correlation between pyrazinamide dose (i.e. 21.4 - 35.7 mg/kg/day) and drug exposure (AUC ranging from 220.6 to 514.5 mg⋅h/L). Additionally, human studies confirmed a dose-effect relationship with an increased two-month sputum culture conversion rate at AUC/MIC targets of 8.4 -11.3 with higher exposure/susceptibility ratios leading to greater efficacy. A 5-fold variability in AUC was observed at pyrazinamide dose of 25 mg/kg. A direct concentration - effect relationship and increased treatment efficacy with higher pyrazinamide exposure to susceptibility ratios was observed. Taking into account the variability in drug exposure and treatment response further studies on dose optimization are justified.