Novartis Pharma AG, Basel, Switzerland.
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Clin Pharmacol Drug Dev. 2018 Aug;7(6):575-586. doi: 10.1002/cpdd.459. Epub 2018 Apr 25.
This open-label, single-sequence study in healthy subjects investigated the effects of steady-state carbamazepine on the pharmacokinetic (PK) profile of a single 2-mg dose of fingolimod. In period 1, a single oral dose of fingolimod 2 mg (day 1) was followed by PK and safety assessments up to 36 days. In period 2, carbamazepine was administered in flexible, up-titrated doses (600 mg twice daily maximum) for 49 days. Fingolimod was administered on day 35, followed by a study completion evaluation (day 71). The PK analysis included 23 of 26 of the enrolled subjects (88.5%). Coadministration of fingolimod at steady-state carbamazepine concentrations resulted in increased fingolimod CL/F by 67% through the induction of CYP3A4, a cytochrome with negligible involvement in fingolimod clearance in an uninduced state. Fingolimod C was reduced by 18% and AUC by 40%, as was T (106 vs 163 hours). A similar trend was observed for fingolimod-P. Models linking fingolimod-P blood concentrations to lymphocyte count or annual relapse rate suggest that such a decrease would have a low impact on the treatment effect. However, in the absence of efficacy data of fingolimod at doses lower than the therapeutic dose, their coadministration should be used with caution.
这项在健康受试者中进行的开放性、单序列研究旨在考察卡马西平稳态对单剂量 2mg 芬戈莫德药代动力学（PK）特征的影响。在第 1 个周期中，受试者单次口服 2mg 芬戈莫德（第 1 天），随后进行 PK 评估和安全性评估，持续 36 天。在第 2 个周期中，卡马西平以灵活的增量剂量（最大剂量为 600mg，每日 2 次）给药 49 天。第 35 天给予芬戈莫德，随后进行研究完成评估（第 71 天）。PK 分析包括 26 名入组受试者中的 23 名（88.5%）。在卡马西平稳态浓度下同时给予芬戈莫德可使 CYP3A4 诱导，使芬戈莫德 CL/F 增加 67%，而 CYP3A4 在未诱导状态下对芬戈莫德清除的参与可忽略不计。芬戈莫德 C 减少 18%，AUC 减少 40%，T（106 与 163 小时）也减少。芬戈莫德-P 也观察到类似的趋势。将芬戈莫德-P 血药浓度与淋巴细胞计数或年复发率联系起来的模型表明，这种减少对治疗效果的影响较低。然而，在缺乏低于治疗剂量的芬戈莫德疗效数据的情况下，应谨慎联合使用。
