te Brake L H M, Ruslami R, Later-Nijland H, Mooren F, Teulen M, Apriani L, Koenderink J B, Russel F G, Burger D M, Alisjahbana B, Wieringa F, van Crevel R, Aarnoutse R E
Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands
Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin Hospital, Bandung, Indonesia.
Antimicrob Agents Chemother. 2015;59(6):3233-9. doi: 10.1128/AAC.03485-14. Epub 2015 Mar 23.
Nutritional status may have a profound impact on the pharmacokinetics of drugs, yet only few data are available for tuberculosis (TB) drugs. As malnutrition occurs frequently among TB patients, we assessed the effect of malnutrition on the steady-state pharmacokinetics of total and protein-unbound rifampin during the intensive phase of TB treatment. In a descriptive pharmacokinetic study in Bandung, Indonesia, patients received a fixed standard rifampin dose of 450 mg once daily during the intensive phase of TB treatment. A full pharmacokinetic curve for rifampin was recorded, and total and unbound concentrations of rifampin were analyzed in all samples. Rifampin pharmacokinetic parameters were compared between severely malnourished (BMI of <16.0 kg/m(2)), malnourished (BMI of <18.5 kg/m(2)), and well-nourished (BMI of ≥18.5 kg/m(2)) individuals. No difference in total and protein-unbound pharmacokinetic parameters between severely malnourished (n = 7), malnourished (n = 11), and well-nourished (n = 25) patients could be demonstrated. In addition, no significant correlation between BMI and exposure (area under the concentration-time curve from 0 to 24 h [AUC0-24] and maximum concentration of drug in serum [Cmax]) was found. Females had significantly higher total AUC0-24 (geometric mean, 59.2 versus 48.2 h · mg/liter; P = 0.02) and higher unbound AUC0-24 (geometric mean, 6.2 versus 4.8 h · mg/liter; P = 0.02) than males. Overall, a marked 2-fold interindividual variation in the free fraction was observed (7.6 to 15.0%; n = 36). Nutritional status and BMI do not appear to have a major effect on total and protein-unbound pharmacokinetic parameters of rifampin in Indonesian subjects. The large interindividual variability in the free fraction of rifampin suggests that protein-unbound rather than total rifampin concentrations should preferably be used to study exposure-response relationships.
营养状况可能对药物的药代动力学产生深远影响，但关于抗结核药物的相关数据却十分有限。由于营养不良在结核病患者中较为常见，我们评估了营养不良对结核病治疗强化期利福平稳态药代动力学的影响。在印度尼西亚万隆进行的一项描述性药代动力学研究中，患者在结核病治疗强化期每天接受一次固定标准剂量450毫克的利福平。记录了利福平的完整药代动力学曲线，并对所有样本中的利福平总浓度和游离浓度进行了分析。比较了严重营养不良（体重指数<16.0kg/m²）、营养不良（体重指数<18.5kg/m²）和营养良好（体重指数≥18.5kg/m²）个体之间的利福平药代动力学参数。结果显示，严重营养不良患者（n = 7）、营养不良患者（n = 11）和营养良好患者（n = 25）之间的利福平总浓度和游离浓度药代动力学参数并无差异。此外，未发现体重指数与药物暴露（0至24小时浓度 - 时间曲线下面积[AUC0 - 24]和血清中药物最大浓度[Cmax]）之间存在显著相关性。女性的总AUC0 - 24显著高于男性（几何均值分别为59.2和48.2小时·毫克/升；P = 0.02），游离AUC0 - 24也更高（几何均值分别为6.2和4.8小时·毫克/升；P = 0.02）。总体而言，观察到游离分数存在显著的2倍个体间差异（7.6%至15.0%；n = 36）。在印度尼西亚受试者中，营养状况和体重指数似乎对利福平的总浓度和游离浓度药代动力学参数没有重大影响。利福平游离分数的个体间差异较大，这表明在研究暴露 - 反应关系时，最好使用游离利福平浓度而非总浓度。
