UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9113, USA.
Antimicrob Agents Chemother. 2010 Jul;54(7):2847-54. doi: 10.1128/AAC.01567-09. Epub 2010 May 3.
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 (Cochrane Q statistic P value of <0.001; I(2) of >95%). For the once-a-day dosing schedule, arthralgia was dose dependent (r(2) = 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.
抗微生物药代动力学-药效学研究表明，高于目前建议剂量的吡嗪酰胺可能更有效。然而，高剂量吡嗪酰胺被认为具有肝毒性。在 MEDLINE、EBSCOHOST 和 Cochrane 对照试验登记处进行了临床试验搜索。检查了采用吡嗪酰胺剂量方案和药代动力学分析设计的研究。利用群体药代动力学建模方法来确定与毒性相关的参数。在等效浓度-时间曲线下面积时，浓度持续高于某些阈值的时间与总体不良事件（P = 0.032）、关节炎（P = 0.089）和 3 个月时血清天冬氨酸氨基转移酶水平升高（P = 0.067）相关。接下来，利用荟萃分析比较了（i）不同吡嗪酰胺剂量之间、（ii）不同给药方案之间以及（iii）含吡嗪酰胺和不含吡嗪酰胺的抗结核方案之间的不良事件发生率。选择的 29 项研究具有异质性（Cochrane Q 统计量 P 值<0.001；I（2）>95%）。对于每日一次给药方案，关节炎与剂量有关（r（2）= 0.996）。然而，间歇性给药时关节炎较少见，这与浓度持续高于阈值的时间一致。关节炎通常无临床意义。吡嗪酰胺单药治疗的肝毒性发生率为 0.057（95%置信区间 [CI]，0.021 至 0.141），含吡嗪酰胺的联合方案为 0.044（CI，0.033 至 0.059），不含吡嗪酰胺的联合方案为 0.040（CI，0.023 至 0.040）。吡嗪酰胺的体重 30mg/kg 时肝毒性发生率为 0.042（CI，0.026 至 0.067），体重 40mg/kg 时为 0.055（CI，0.031 至 0.094），体重 60mg/kg 时为 0.098（CI，0.047 至 0.193）。因此，高剂量吡嗪酰胺并未显著增加肝毒性。这表明部分肝毒性发生率可能是特发性的。
