Clinical and Toxicodynamic Evidence that High-Dose Pyrazinamide Is Not More Hepatotoxic than the Low Doses Currently Used

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Abstract
Antimicrobial pharmacokinetic-pharmacodynamic studies suggest that pyrazinamide doses higher than those currently recommended may be more efficacious. However, high pyrazinamide doses are believed to be hepatotoxic. Searches for clinical trials in MEDLINE, EBSCOHOST, and the Cochrane Controlled Trial Register were made. Studies that employed pyrazinamide dose scheduling and pharmacokinetic analysis design were examined. Population pharmacokinetic modeling methods were utilized to identify parameters associated with toxicity. At an equivalent area under the concentration-time curve, the time that concentration persisted above some thresholds was associated with overall adverse events (P= 0.032), arthralgia (P= 0.089), and an elevated serum aspartate aminotransferase level at 3 months (P= 0.067). Next, a meta-analysis was utilized to compare rates of adverse events (i) between different pyrazinamide doses, (ii) between different dosing schedules, and (iii) between pyrazinamide-containing and non-pyrazinamide-containing antituberculosis regimens. The 29 studies selected were heterogeneous (CochraneQstatisticPvalue of 95%). For the once-a-day dosing schedule, arthralgia was dose dependent (r2= 0.996). However, arthralgia was less common with intermittent dosing, consistent with the time concentration persisted above the threshold. Arthralgia was generally clinically inconsequential. The frequencies of hepatotoxicity were 0.057 (95% confidence interval [CI], 0.021 to 0.141) for pyrazinamide monotherapy, 0.044 (CI, 0.033 to 0.059) for pyrazinamide-containing combination regimens, and 0.040 (CI, 0.023 to 0.040) for non-pyrazinamide-containing combination regimens. The frequencies of hepatotoxicity were 0.042 (CI, 0.026 to 0.067) for 30 mg/kg of body weight, 0.055 (CI, 0.031 to 0.094) at 40 mg/kg, and 0.098 (CI, 0.047 to 0.193) at 60 mg/kg of pyrazinamide. Thus, high-dose pyrazinamide did not significantly increase hepatotoxicity. This suggests that a considerable portion of hepatotoxicity rates may be idiosyncratic.