Effect of age on the pharmacokinetics of duloxetine in women

Abstract

Aims: The effect of age on duloxetine pharmacokinetics was evaluated in healthy volunteers and in patients with urinary incontinence.

Methods: 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).

Results: 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.

Conclusions: 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.

Figure 1

Individual () and mean (•) plasma concentration-time profiles of duloxetine obtained from elderly and younger subjects administered a single oral 40-mg dose of duloxetine.

Figure 2

Individual and mean (—) apparent plasma clearances of duloxetine in elderly (65 to 77 years (○)) and younger (32 to 50 years (•)) subjects. (The error bar represents 1 SD, mean ± SD.)

Figure 3

Scatter plots of individual predicted vs. observed concentrations and individual weighted residuals vs. individual predicted concentrations.

Figure 4

The relationship of apparent plasma clearance with age in patients with urinary incontinence. Individual estimates (○); and predicted values (—).