Pharmacokinetics, Tolerability, and Bacteriological Response of Rifampin Administered at 600, 900, and 1,200 Milligrams Daily in Patients with Pulmonary Tuberculosis
Pharmacokinetics, Tolerability, and Bacteriological Response of Rifampin Administered at 600, 900, and 1,200 Milligrams Daily in Patients with Pulmonary Tuberculosis
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DOI：
10.1128/aac.01054-17
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发表时间：
2017-11-01
影响因子：
4.9
通讯作者：
Boeree, M. J.
中科院分区：
文献类型：
--
作者：
Aarnoutse, R. E.;Kibiki, G. S.;Boeree, M. J.
在一项多剂量范围试验中，我们之前评估了患者服用较高剂量的利福平两周。本研究的目的是在较长时间内服用更高剂量的利福平，以比较此类方案的药代动力学、安全性/耐受性和细菌学活性。在一项双盲、随机、安慰剂对照、II 期临床试验中，150 名坦桑尼亚结核病 (TB) 患者被随机分配接受 600 mg（约 10 mg/kg 体重）、900 mg 或 1,200 mg 利福平联合标准剂量的异烟肼、吡嗪酰胺和乙胺丁醇，每日服用，持续 2 个月。治疗 6 周后，对 63 名患者进行了密集的药代动力学采样，并评估了安全性/耐受性。通过液体和固体培养基中的培养物转化来评估细菌学反应。几何平均总暴露量（给药后 24 小时内浓度与时间曲线下的面积）分别为 24.6、50.8 和 76.1 mg。 600 mg、900 mg 和 1,200 mg 组分别为 h/L，反映了暴露随剂量的非线性增加 (P < 0.001)。 600 mg 组仅发生 2 名患者，900 mg 组有 4 名患者，1,200 mg 组有 5 名患者发生 3 级不良事件。没有观察到细菌学反应的显着差异。每日较高剂量的利福平（900 和 1,200 mg）会导致血浆中利福平暴露超比例增加，与其他一线抗结核药物联合使用 2 个月时是安全且耐受性良好的，但并没有改善肺结核患者的细菌学反应。这些发现有必要在后续试验中评估更高剂量的利福平。
In a multiple-dose-ranging trial, we previously evaluated higher doses of rifampin in patients for 2 weeks. The objectives of the current study were to administer higher doses of rifampin for a longer period to compare the pharmacokinetics, safety/tolerability, and bacteriological activity of such regimens. In a double-blind, randomized, placebo-controlled, phase II clinical trial, 150 Tanzanian patients with tuberculosis (TB) were randomized to receive either 600 mg (approximately 10 mg/kg of body weight), 900 mg, or 1,200 mg rifampin combined with standard doses of isoniazid, pyrazinamide, and ethambutol administered daily for 2 months. Intensive pharmacokinetic sampling occurred in 63 patients after 6 weeks of treatment, and safety/tolerability was assessed. The bacteriological response was assessed by culture conversion in liquid and solid media. Geometric mean total exposures (area under the concentration-versus-time curve up to 24 h after the dose) were 24.6, 50.8, and 76.1 mg . h/liter in the 600-mg, 900-mg, and 1,200-mg groups, respectively, reflecting a nonlinear increase in exposure with the dose (P < 0.001). Grade 3 adverse events occurred in only 2 patients in the 600-mg arm, 4 patients in the 900-mg arm, and 5 patients in the 1,200-mg arm. No significant differences in the bacteriological response were observed. Higher daily doses of rifampin (900 and 1,200 mg) resulted in a more than proportional increase in rifampin exposure in plasma and were safe and well tolerated when combined with other first-line anti-TB drugs for 2 months, but they did not result in improved bacteriological responses in patients with pulmonary TB. These findings have warranted evaluation of even higher doses of rifampin in follow-up trials.