Duloxetine 60 mg twice daily is a moderately potent CYP2D6 inhibitor, intermediate between paroxetine and sertraline. The potent CYP2D6 inhibitor paroxetine has a moderate effect on duloxetine concentrations. The results of these 2 studies suggest that caution should be used when CYP2D6 substrates and inhibitors are coadministered with duloxetine.

AimsThe effect of age on duloxetine pharmacokinetics was evaluated in healthy volunteers and in patients with urinary incontinence. MethodsTwenty-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 concentrationtime 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 prog ram (NONMEM). ResultsIn Study 1, the elderly ( ≥ 65 years) exhibited a statistically significant slower elimination rate constant l z 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. ConclusionsWhereas the results suggest that age has an effect on duloxetine pharmacokinetics, primarily reflected as a slower l z 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. Effect of age on the pharmacokinetics of duloxetine in womenBr J Clin Pharmacol 57 :1 55

Dose adjustments for duloxetine are not necessary for patients with mild or moderate renal impairment (CL(CR) > or =30 mL/min). For patients with ESRD or severe renal impairment (CL(CR) <30 mL/min), exposures of duloxetine and its metabolites are expected to increase; therefore, duloxetine is not generally recommended for these patients.