Skinner Michael H, Kuan Han-Yi, Skerjanec Andrej, Seger Mary E, Heathman Michael, O'Brien Lisa, Reddy Shobha, Knadler Mary P
Lilly Laboratory for Clinical Research, Indiana University Hospital and Outpatient Center, Indianapolis, IN 46202, USA.
Br J Clin Pharmacol. 2004 Jan;57(1):54-61. doi: 10.1046/j.1365-2125.2003.01963.x.
The effect of age on duloxetine pharmacokinetics was evaluated in healthy volunteers and in patients with urinary incontinence.
Twenty-four healthy subjects (12 women 65-77 years, and 12 women 32-50 years) were given a single 40-mg oral dose of duloxetine in Study 1. Plasma concentration-time data were analysed by noncompartmental pharmacokinetic methods. Sparse plasma samples were obtained from patients with urinary incontinence treated in two phase II studies: 70 women (24-77 years) who received duloxetine 20 mg day(-1), 30 mg day(-1), or 40 mg day(-1) in Study 2A and 128 women (28-64 years) who received duloxetine 20 mg day(-1), 40 mg day(-1), or 80 mg day(-1) in Study 2B. Based upon the combined data, a model was developed to characterize population pharmacokinetics of duloxetine using the nonlinear mixed-effects modelling program (NONMEM).
In Study 1, the elderly (> or = 65 years) exhibited a statistically significant slower elimination rate constant lambdaz compared with younger subjects [elderly-younger difference = -0.022 h(-1)[95% confidence interval (CI) -0.036, -0.008]]. However, no statistically significant differences in either CL/F [elderly-younger difference = -17.4 l h(-1) (95% CI -41.1, 6.23)] or V/F [elderly-younger difference = 115.9 l (95% CI -168.6, 400.4)] were observed. The population pharmacokinetic analysis of Studies 2A and 2B revealed that the CL/F of duloxetine decreased with increasing age. Despite statistical significance, the age effect only accounted for 3% of the interindividual variability in CL/F and unexplained sources of the variation in clearance were still substantial (> 50%). Adverse events were generally mild to moderate, and the incidence of adverse events was generally similar in elderly and non-elderly participants in these studies.
Whereas the results suggest that age has an effect on duloxetine pharmacokinetics, primarily reflected as a slower lambdaz in the elderly, the magnitude of mean changes in CL/F, or V/F was small relative to the large interindividual variation in pharmacokinetics. Elderly participants had a safety profile of duloxetine comparable to their younger counterparts. Specific dose recommendations for duloxetine in the elderly are not warranted.
在健康志愿者和尿失禁患者中评估年龄对度洛西汀药代动力学的影响。
在研究1中，24名健康受试者（12名65 - 77岁女性和12名32 - 50岁女性）口服40 mg单剂量度洛西汀。采用非房室药代动力学方法分析血浆浓度-时间数据。从两项II期研究中接受治疗的尿失禁患者中获取稀疏血浆样本：研究2A中70名女性（24 - 77岁）接受度洛西汀20 mg/天、30 mg/天或40 mg/天治疗，研究2B中128名女性（28 - 64岁）接受度洛西汀20 mg/天、40 mg/天或80 mg/天治疗。基于合并数据，使用非线性混合效应建模程序（NONMEM）建立模型来表征度洛西汀的群体药代动力学。
在研究1中，老年人（≥65岁）与年轻受试者相比，消除速率常数λz在统计学上显著较慢[老年 - 年轻差异 = -0.022 h⁻¹[95%置信区间（CI）-0.036，-0.008]]。然而，在CL/F[老年 - 年轻差异 = -17.4 l/h（95% CI -41.1，6.23）]或V/F[老年 - 年轻差异 = 115.9 l（95% CI -168.6，400.4）]方面未观察到统计学上的显著差异。研究2A和2B的群体药代动力学分析显示，度洛西汀的CL/F随年龄增加而降低。尽管具有统计学意义，但年龄效应仅占CL/F个体间变异性的3%，清除率变化的未解释来源仍然很大（>50%）。不良事件一般为轻度至中度，在这些研究中，老年和非老年参与者的不良事件发生率总体相似。
虽然结果表明年龄对度洛西汀药代动力学有影响，主要表现为老年人的λz较慢，但相对于药代动力学中较大的个体间差异，CL/F或V/F的平均变化幅度较小。老年参与者的度洛西汀安全性与年轻参与者相当。无需针对老年人制定度洛西汀的具体剂量建议。
