Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Uxbridge, United Kingdom.
Antimicrob Agents Chemother. 2012 Nov;56(11):5442-9. doi: 10.1128/AAC.05988-11. Epub 2012 Jul 9.
Historically, dosing regimens for the treatment of tuberculosis (TB) have been proposed in an empirical manner. Dose selection has often been the result of efficacy trials in which drugs were administered regardless of the magnitude of the effect of demographic factors on drug disposition. This has created challenges for the prescription of fixed-dose combinations with novel therapeutic agents. The objectives of this investigation were to evaluate the impact of body weight on the overall systemic exposure to pyrazinamide (PZA) and to assess whether the use of one fixed dose, without adjustment according to weight, would ensure target exposure and safety requirements across the overall patient population. Using a population pharmacokinetic model, simulation scenarios were explored based on population demographics from clinical trials in TB patients and on historical hepatotoxicity data. The systemic drug exposure (area under the concentration-time curve [AUC]), peak concentrations (the maximum concentration of drug in serum [C(max)]), the time above the MIC (t > MIC), and the risk of hepatotoxicity were evaluated for the current weight-banded regimen and compared to fixed doses under the assumption that pharmacokinetic differences are the primary drivers of toxicity. Evaluation of the standard weight banding reveals that more than 50% of subjects in the weight range of 45 to 55 kg remain below the proposed target exposure to PZA. In contrast, the use of a fixed 1,500-mg dose resulted in a lower proportion of subjects under the target value, with a 0.2% average overall increase in the risk of hepatotoxicity. Our results strongly support the use of a fixed-dose regimen for PZA in coformulation or combination with novel therapeutic agents.
从历史上看，结核病（TB）的治疗方案是通过经验提出的。剂量选择通常是疗效试验的结果，在这些试验中，无论人口因素对药物处置的影响有多大，都会给予药物。这给新型治疗药物的固定剂量组合的处方带来了挑战。本研究的目的是评估体重对吡嗪酰胺（PZA）全身暴露的总体影响，并评估是否使用一个固定剂量，而不根据体重进行调整，是否可以确保整个患者群体的目标暴露和安全性要求。本研究使用群体药代动力学模型，根据 TB 患者临床试验中的人群统计学数据和历史肝毒性数据，探讨了基于模拟场景的方案。评估了当前体重分组方案的全身药物暴露（浓度-时间曲线下面积 [AUC]）、峰值浓度（血清中药物的最大浓度 [C(max)]）、高于 MIC 时间（t > MIC）以及肝毒性风险，与假设药代动力学差异是毒性的主要驱动因素的固定剂量进行了比较。对标准体重分组的评估表明，体重在 45 至 55 公斤范围内的受试者中有超过 50%的人仍低于 PZA 建议的目标暴露量。相比之下，使用固定的 1500 毫克剂量会导致更多的受试者低于目标值，肝毒性风险平均增加 0.2%。我们的结果强烈支持在新型治疗药物的联合用药中使用固定剂量的 PZA 方案。
