Department of Pharmacy, National Cancer Center Hospital East, Japan.
School of Pharmaceutical Sciences, Ohu University, Japan.
Drug Res (Stuttg). 2020 May;70(5):199-205. doi: 10.1055/a-1122-8129. Epub 2020 Mar 19.
In Japan, tuberculosis has been recognized as one of the major infections requiring urgent measures because of its high morbidity rate even now especially in elderly people suffering from tuberculosis during the past epidemic and its reactivation. Hence, many Japanese clinicians have made efforts to suppress the onset of tuberculosis and treat it effectively. The objectives of this study are to (1) identify covariate(s) that may explain the variation of rifampicin, which is the key antitubercular agent, under the steady-state by evaluating its population pharmacokinetics and (2) to propose an appropriate dosing method of rifampicin to Japanese patients. For this purpose, serum concentration-time data were obtained from 138 patients receiving rifampicin (300-450 mg) and isoniazid (300-400 mg) every day over 14 days, and analyzed using nonlinear mixed effects model. Thereby, population pharmacokinetic parameters were estimated followed by elucidating relations between the parameters and statistical factors. The analysis adopted one-compartment model including Lag-time by assuming that the absorption process is 0+1st order. The analyses demonstrate that meal affected the bioavailability, primary absorption rate constant, and zero order absorption time in the constructed model. A body weight calculated from the power model was selected as the covariate by the Stepwise Covariate Model method and found to highly affect the clearance in the range from -31.6% to 47.4%. We conclude that the dose in Japanese tuberculous patients can be well estimated by the power model formula and should be taken into consideration when rifampicin is administered.
在日本，结核病因其发病率高而被认为是需要采取紧急措施的主要传染病之一，尤其是在过去流行期间患有结核病的老年人和其复发的情况下。因此，许多日本临床医生努力抑制结核病的发病并有效治疗它。本研究的目的是：(1) 通过评估其群体药代动力学，确定可能解释利福平（关键抗结核药物）在稳态下变化的协变量；(2) 为日本患者提出利福平的适当给药方法。为此，对 138 例每天接受利福平（300-450mg）和异烟肼（300-400mg）治疗 14 天的患者的血清浓度-时间数据进行了评估，并使用非线性混合效应模型进行了分析。由此，估计了群体药代动力学参数，并阐明了参数与统计因素之间的关系。分析采用了包括滞后时间的单室模型，假设吸收过程为 0+1 级。分析表明，膳食影响了构建模型中的生物利用度、初始吸收速率常数和零级吸收时间。通过逐步协变量模型方法，选择了幂模型计算的体重作为协变量，发现其在 -31.6%至 47.4%的范围内对清除率有显著影响。我们得出结论，日本结核病患者的剂量可以通过幂模型公式很好地估计，在给予利福平时应考虑到这一点。
