Swanson Rosemary V, Adamson John, Moodley Chivonne, Ngcobo Bongani, Ammerman Nicole C, Dorasamy Afton, Moodley Sashen, Mgaga Zinhle, Tapley Asa, Bester Linda A, Singh Sanil, Grosset Jacques H, Almeida Deepak V
KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.
KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
Antimicrob Agents Chemother. 2015;59(6):3042-51. doi: 10.1128/AAC.00260-15. Epub 2015 Mar 9.
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 μg/g in all tissues by 4 weeks of administration, while serum drug levels remained low at 1 to 2 μg/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.
抗麻风病药物氯法齐明已显示出缩短结核病治疗时间的潜力；然而，目前该药物的给药剂量并非基于证据，最佳剂量尚不清楚。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估，目的是为未来研究的给药提供有用信息。在感染和未感染的BALB/c小鼠中评估药代动力学参数。在感染结核分枝杆菌的小鼠中评估药效学参数，这些小鼠用六种不同的氯法齐明给药方案之一治疗12周，即体重每天6.25、12.5和25mg/kg的剂量以及三种负荷剂量方案。氯法齐明在小鼠的肺、肝和脾中逐渐蓄积，给药4周后所有组织中的水平均超过50μg/g，而血清药物水平保持在1至2μg/ml的低水平。氯法齐明的消除极其缓慢，半衰期取决于给药持续时间。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，但随后表现出强效、剂量无关的杀菌活性。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，这表明可以使用低得多的剂量有效治疗结核病。
