Pharmacokinetics and Pharmacodynamics of Clofazimine in a Mouse Model of Tuberculosis
Pharmacokinetics and Pharmacodynamics of Clofazimine in a Mouse Model of Tuberculosis
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DOI：
10.1128/aac.00260-15
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发表时间：
2015-06-01
影响因子：
4.9
通讯作者：
Almeida, Deepak V.
中科院分区：
文献类型：
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作者：
Swanson, Rosemary V.;Adamson, John;Almeida, Deepak V.
抗麻风病药物氯法齐明已显示出缩短结核病治疗的潜力;然而，该药物目前的剂量没有证据，最佳剂量未知。我们的目标是在结核病小鼠模型中对氯法齐明的药代动力学和药效学进行临床前评价，目的是为未来的研究提供有用的剂量信息。在感染和未感染的BALB/c小鼠中评价药代动力学参数。在用六种不同的氯法齐明给药方案之一治疗12周的结核分枝杆菌感染的小鼠中评价药效学参数，即，6.25、12.5和25 mg/kg体重/天剂量和3种负荷剂量方案。氯法齐明在小鼠的肺、肝和脾中逐渐积累，在给药4周时在所有组织中达到大于50 μ g/g的水平，而血清药物水平保持在1至2 μ g/ml的低水平。氯法齐明的消除非常缓慢，半衰期取决于给药的持续时间。氯法齐明表现出剂量依赖性的组织和血清浓度。在任何剂量下，氯法齐明在给药的前2周内均无杀菌活性，但随后显示出强效、剂量依赖性杀菌活性。氯法齐明的抗结核活性既不依赖于给药剂量，也不依赖于组织中的药物浓度，这表明低得多的剂量可以有效地用于结核病治疗。
The antileprosy drug clofazimine has shown potential for shortening tuberculosis treatment; however, the current dosing of the drug is not evidence based, and the optimal dosing is unknown. Our objective was to conduct a preclinical evaluation of the pharmacokinetics and pharmacodynamics of clofazimine in the mouse model of tuberculosis, with the goal of providing useful information on dosing for future studies. Pharmacokinetic parameters were evaluated in infected and uninfected BALB/c mice. Pharmacodynamic parameters were evaluated in Mycobacterium tuberculosis-infected mice that were treated for 12 weeks with one of six different clofazimine dosing regimens, i.e., doses of 6.25, 12.5, and 25 mg/kg of body weight/day and 3 regimens with loading doses. Clofazimine progressively accumulated in the lungs, livers, and spleens of the mice, reaching levels of greater than 50 mu g/g in all tissues by 4 weeks of administration, while serum drug levels remained low at 1 to 2 mu g/ml. Elimination of clofazimine was extremely slow, and the half-life was dependent on the duration of drug administration. Clofazimine exhibited dose-dependent tissue and serum concentrations. At any dose, clofazimine did not have bactericidal activity during the first 2 weeks of administration but subsequently demonstrated potent, dose-independent bactericidal activity. The antituberculosis activity of clofazimine was dependent on neither the dose administered nor the drug concentrations in the tissues, suggesting that much lower doses could be effectively used for tuberculosis treatment.