title: Effect of age on the pharmacokinetics of duloxetine in women.
abstract: OBJECTIVE
  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.
authors.affiliation: Lilly Laboratory for Clinical Research, Indiana University Hospital and Outpatient Center, Indianapolis, IN 46202, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Skinner
authors.forename: Han-Yi
authors.initials: HY
authors.lastname: Kuan
authors.forename: Andrej
authors.initials: A
authors.lastname: Skerjanec
authors.forename: Mary E
authors.initials: ME
authors.lastname: Seger
authors.forename: Michael
authors.initials: M
authors.lastname: Heathman
authors.forename: Lisa
authors.initials: L
authors.lastname: O'Brien
authors.forename: Shobha
authors.initials: S
authors.lastname: Reddy
authors.forename: Mary P
authors.initials: MP
authors.lastname: Knadler
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000328:Adult; D000368:Aged; D000375:Aging / Q000378:metabolism*; D000068736:Duloxetine Hydrochloride; D005260:Female; D006801:Humans; D008875:Middle Aged; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013876:Thiophenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014549:Urinary Incontinence / Q000097:blood / Q000188:drug therapy / Q000378:metabolism
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000068736:Duloxetine Hydrochloride; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes