Clinical Pharmacology Department, Cephalon, Inc., Frazer, Pennsylvania 19355, USA.
Drugs Aging. 2011 Feb 1;28(2):139-50. doi: 10.2165/11586370-000000000-00000.
Armodafinil (Nuvigil(®), Cephalon, Inc., Frazer, PA, USA), the longer-lasting isomer of racemic modafinil, is a nonamphetamine, wakefulness-promoting medication. In patients with excessive sleepiness associated with shift work disorder, treated obstructive sleep apnoea, or narcolepsy, armodafinil has been found to improve wakefulness throughout the shift or day. In addition, while not approved for this indication, armodafinil has been found to improve excessive sleepiness associated with jet-lag disorder.
This study evaluated systemic exposure to armodafinil and its two major circulating metabolites, R-modafinil acid and modafinil sulfone, and assessed the tolerability profile of armodafinil in elderly and young subjects.
The pharmacokinetics and tolerability of armodafinil were assessed in an open-label, multiple-dose, parallel-group study in two groups (n = 25 in each group) of healthy men (elderly group aged ≥65 years and young group aged 18-45 years) who received armodafinil 50 mg on day 1, 100 mg on day 2 and 150 mg once daily on days 3 through 7. Plasma concentrations of armodafinil and its metabolites were quantified over 72 hours following the last dose on day 7. Pharmacokinetic parameters, including area under the plasma drug concentration-versus-time curve during a dosing interval (AUC(τ)) and maximum observed plasma drug concentration (C(max)), and tolerability were assessed.
All 50 subjects enrolled in the study were evaluable for tolerability and 49 were included in the pharmacokinetic analysis. One elderly subject was excluded from the pharmacokinetic analyses because of apparent noncompliance with armodafinil dosing. Systemic exposure following administration of armodafinil, as measured by steady-state AUC(τ) and C(max) values, was approximately 15% greater in elderly subjects compared with young subjects. Geometric mean ratios for AUC(τ) and C(max) in the two groups were 1.14 (95% CI 1.03, 1.25; p = 0.0086) and 1.15 (95% CI 1.08, 1.24; p = 0.0002), respectively. When data were analysed for elderly subgroups, systemic exposure in the old-elderly group (age ≥75 years; n = 7) was 27% greater than in young subjects, as compared with 10% greater in the young-elderly group (age 65-74 years; n = 17). Although steady-state exposure to the metabolite R-modafinil acid was also higher in elderly than in young subjects (geometric mean ratios for AUC(τ) and C(max) were 1.73 and 1.61, respectively; p < 0.0001), there were no significant differences in systemic exposure to modafinil sulfone. Armodafinil was generally well tolerated by both groups. Headache (four subjects in each group), nausea (one in the elderly group and four in the young group), insomnia (two in the elderly group and one in the young group), and dizziness (two in the young group) were the most common adverse events.
Systemic exposure following administration of armodafinil is increased in the elderly in comparison with younger subjects, particularly in those aged ≥75 years. Although the increase in plasma armodafinil concentration in elderly subjects does not appear to result in more adverse events compared with young subjects, consideration should be given to the use of lower dosages of armodafinil for the management of excessive sleepiness in older patients, particularly the very elderly.
阿莫达非尼（Nuvigil®， Cephalon，Inc.，Frazer，PA，USA）是一种长效的立体异构体，是非安非他命类促清醒药物。在与轮班工作障碍、阻塞性睡眠呼吸暂停或发作性睡病相关的过度嗜睡患者中，阿莫达非尼被发现可以改善整个轮班或白天的清醒度。此外，虽然未批准用于该适应症，但已发现阿莫达非尼可改善与时差障碍相关的过度嗜睡。
本研究评估了阿莫达非尼及其两种主要循环代谢物 R-阿莫达非尼酸和阿莫达非尼砜在老年和年轻受试者中的系统暴露情况，并评估了阿莫达非尼的耐受性。
在一项开放标签、多剂量、平行组研究中，评估了健康男性（老年组年龄≥65 岁，年轻组年龄 18-45 岁）中阿莫达非尼的药代动力学和耐受性，两组各有 25 名受试者。受试者在第 1 天接受阿莫达非尼 50mg，第 2 天接受 100mg，第 3 天至第 7 天每天接受 150mg。在第 7 天最后一次给药后 72 小时内定量测定阿莫达非尼及其代谢物的血浆浓度。评估了药代动力学参数，包括剂量间隔期间的血浆药物浓度-时间曲线下面积（AUC(τ)）和最大观察到的血浆药物浓度（C(max)），以及耐受性。
所有 50 名受试者均纳入了耐受性研究，其中 49 名受试者纳入了药代动力学分析。由于明显不遵守阿莫达非尼给药方案，1 名老年受试者被排除在药代动力学分析之外。与年轻受试者相比，老年受试者给药后的系统暴露量（通过稳态 AUC(τ)和 C(max)值测量）大约增加了 15%。两组 AUC(τ)和 C(max)的几何均数比值分别为 1.14（95%CI 1.03，1.25；p=0.0086）和 1.15（95%CI 1.08，1.24；p=0.0002）。当对老年亚组进行数据分析时，与年轻受试者相比，老年组（年龄≥75 岁；n=7）的系统暴露量增加了 27%，而年轻老年组（年龄 65-74 岁；n=17）的系统暴露量增加了 10%。尽管与年轻受试者相比，老年受试者的 R-阿莫达非尼酸代谢物的稳态暴露量也更高（AUC(τ)和 C(max)的几何均数比值分别为 1.73 和 1.61，均<0.0001），但阿莫达非尼砜的系统暴露量没有显著差异。两组受试者均能很好地耐受阿莫达非尼。最常见的不良事件包括头痛（每组 4 例）、恶心（老年组 1 例，年轻组 4 例）、失眠（老年组 2 例，年轻组 1 例）和头晕（年轻组 2 例）。
与年轻受试者相比，阿莫达非尼在老年受试者中的系统暴露量增加，尤其是年龄≥75 岁的老年受试者。尽管老年受试者中阿莫达非尼血浆浓度的增加似乎并没有导致与年轻受试者相比更多的不良事件，但对于老年患者（尤其是非常老年患者）过度嗜睡的治疗，应考虑使用较低剂量的阿莫达非尼。
