氯法齐明包括在治疗利福平/耐药结核病(DR-TB)的药物方案中,但很少有关于其与DR-TB治疗方案中其他药物相互作用的信息。我们评估了氯法齐明和异烟肼之间的药代动力学相互作用,利奈唑胺,左氧氟沙星,和环丝氨酸,剂量为terizidone。在Klerksdorp/Tshepong医院新诊断出患有DR-TB的成年人,南非,在最初的2周内开始使用暂时排除氯法齐明的标准治疗。开始氯法齐明之前和之后3周进行药代动力学采样,使用经过验证的液相色谱-串联质谱法测定药物浓度。在NONMEMv7.5.1中使用群体药代动力学解释数据,以探索氯法齐明联合给药和其他相关协变量对异烟肼药代动力学的影响,利奈唑胺,左氧氟沙星,和环丝氨酸。氯法齐明,异烟肼,利奈唑胺,左氧氟沙星,和环丝氨酸数据可用于16、27、21、21和6名参与者,分别。整个队列的中位年龄和体重为39岁和52公斤,分别。氯法齐明暴露在预期范围内,除了左氧氟沙星外,将其添加到治疗方案中并没有显着影响其他药物的药代动力学,导致间隙减少15%.后验幂大小计算预测我们的样本量有97%,90%,和87%的功率在P<0.05检测30%的异烟肼清除率的变化,利奈唑胺,和环丝氨酸,分别。尽管氯法齐明将左氧氟沙星的曲线下面积增加了19%,这不太可能有很大的临床意义,与其他测试药物缺乏相互作用是令人放心的。
Clofazimine is included in drug regimens to treat rifampicin/drug-resistant tuberculosis (DR-TB), but there is little information about its interaction with other drugs in DR-TB regimens. We evaluated the pharmacokinetic interaction between clofazimine and isoniazid, linezolid, levofloxacin, and cycloserine, dosed as terizidone. Newly diagnosed adults with DR-TB at Klerksdorp/Tshepong Hospital, South Africa, were started on the then-standard treatment with clofazimine temporarily excluded for the initial 2 weeks. Pharmacokinetic sampling was done immediately before and 3 weeks after starting clofazimine, and drug concentrations were determined using validated liquid chromatography-tandem mass spectrometry assays. The data were interpreted with population pharmacokinetics in
NONMEM v7.5.1 to explore the impact of clofazimine co-administration and other relevant covariates on the pharmacokinetics of isoniazid, linezolid, levofloxacin, and cycloserine. Clofazimine, isoniazid, linezolid, levofloxacin, and cycloserine data were available for 16, 27, 21, 21, and 6 participants, respectively. The median age and weight for the full cohort were 39 years and 52 kg, respectively. Clofazimine exposures were in the expected range, and its addition to the regimen did not significantly affect the pharmacokinetics of the other drugs except levofloxacin, for which it caused a 15% reduction in clearance. A posteriori power size calculations predicted that our sample sizes had 97%, 90%, and 87% power at P < 0.05 to detect a 30% change in clearance of isoniazid, linezolid, and cycloserine, respectively. Although clofazimine increased the area under the curve of levofloxacin by 19%, this is unlikely to be of great clinical significance, and the lack of interaction with other drugs tested is reassuring.