Clinical Pharmacokinetics

, Volume 48, Issue 3, pp 189–197 | Cite as

Population Pharmacokinetics of Orally Administered Duloxetine in Patients

Implications for Dosing Recommendation
  • Evelyn D. Lobo
  • Tonya Quinlan
  • Lisa O’Brien
  • Mary Pat Knadler
  • Michael Heathman
Original Research Article


Objectives: The objectives of this analysis were to characterize the pharmacokinetics of duloxetine at steady state in patients, estimate the variability, identify significant covariates that may influence duloxetine pharmacokinetics and provide appropriate dosing recommendations for patients on duloxetine treatment.

Methods: The pharmacokinetic meta-analysis dataset was created from one open-label clinical study and four double-blind, placebo-controlled clinical studies. Duloxetine concentrations (N = 2002) were obtained from 594 patients diagnosed with major depressive disorder (n = 223), diabetic peripheral neuropathic pain (n = 112), stress urinary incontinence (n = 128) and fibromyalgia (n = 131). Patients were given 20–60 mg/day of oral duloxetine once or twice daily (the highest dose studied was 120 mg/day). A population pharmacokinetic model was developed using a nonlinear mixed-effects modelling method. Covariates including bodyweight, age, sex, ethnicity, smoking status, disease condition, dose, dosing regimen and creatinine clearance were tested for their influence on duloxetine pharmacokinetics. The final model was used to predict steady-state duloxetine concentration-time profiles in various patient subgroups.

Results: Duloxetine pharmacokinetics in patients were described by a one-compartmental pharmacokinetic model. The interpatient variability in apparent oral clearance (CL/F) was 59% and the interpatient variability in the apparent volume of distribution after oral administration (Vd/F) was 97%. The residual error was 31%. Sex, smoking status, age and dose had a statistically significant effect on CL/F, whereas the Vd/F was influenced by ethnicity. CL/F was 40% lower in females than in males and 30% lower in nonsmokers than in smokers. CL/F decreased with increasing dose and age. The Vd/F in Hispanic patients was twice that of non-Hispanic patients. Simulations showed a considerable overlap in duloxetine exposure between the identified patient subgroups.

Conclusion: Given the clinically insignificant change in the magnitude of duloxetine steady-state exposure and the considerable overlap in duloxetine exposure between the patient subgroups, specific dose recommendations based on sex, smoking status, age, dose and ethnicity are not warranted.


  1. 1.
    Hunziker ME, Suehs BT, Bettinger TL, et al. Duloxetine hydrochloride: a new dual-acting medication for the treatment of major depressive disorder. Clin Ther 2005; 27(8): 1126–43PubMedCrossRefGoogle Scholar
  2. 2.
    Detke MJ, Wiltse CG, Mallinckrodt CH, et al. Duloxetine in the acute and long-term treatment of major depressive disorder: a placebo- and paroxetine-controlled trial. Eur Neuropsychopharmacol 2004; 14(6): 457–70PubMedCrossRefGoogle Scholar
  3. 3.
    Raskin J, Pritchett YL, Wang F, et al. A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med 2005; 6(5): 346–56PubMedCrossRefGoogle Scholar
  4. 4.
    Dmochowski RR, Miklos JR, Norton PA, et al. Duloxetine versus placebo for the treatment of North American women with stress urinary incontinence. J Urol 2003; 170 (4 Pt1): 1259–63CrossRefGoogle Scholar
  5. 5.
    Pollack MH, Endicott J, Liebowitz M, et al. Examining quality of life in patients with generalized anxiety disorder: clinical relevance and response to duloxetine treatment. J Psychiatr Res 2008; 26(2): 1–16Google Scholar
  6. 6.
    Rynn M, Russell J, Erickson J, et al. Efficacy and safety of duloxetine in the treatment of generalized anxiety disorder: a flexible-dose, progressive-titration, placebo-controlled trial. Depress Anxiety 2008; 25(3): 182–9PubMedCrossRefGoogle Scholar
  7. 7.
    Arnold LM, Rosen A, Pritchett YL, et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain 2005; 119(1–3): 5–15PubMedCrossRefGoogle Scholar
  8. 8.
    Chan C, Yeo KP, Pan AX, et al. Duloxetine pharmacokinetics are similar in Japanese and Caucasian subjects. Br J Clin Pharmacol 2007; 63(3): 310–14PubMedCrossRefGoogle Scholar
  9. 9.
    Tianmei S, Knadler MP, Lim MT, et al. Pharmacokinetics and tolerability of duloxetine following oral administration to healthy Chinese subjects. Clin Pharmacokinet 2007; 46(9): 767–75PubMedCrossRefGoogle Scholar
  10. 10.
    Skinner MH, Kuan HY, Skerjanec A, et al. Effect of age on the pharmacokinetics of duloxetine in women. Br J Clin Pharmacol 2004; 57(1): 54–61PubMedCrossRefGoogle Scholar
  11. 11.
    Sharma A, Goldberg MJ, Cerimele BJ. Pharmacokinetics and safety of duloxetine, a dual-serotonin and norepinephrine reuptake inhibitor. J Clin Pharmacol 2000; 40(2): 161–7PubMedCrossRefGoogle Scholar
  12. 12.
    Skinner MH, Kuan HY, Pan A, et al. Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers. Clin Pharmacol Ther 2003; 73(3): 170–7PubMedCrossRefGoogle Scholar
  13. 13.
    Gahimer J, Wernicke J, Yalcin I, et al. A retrospective pooled analysis of duloxetine safety in 23,983 subjects. Curr Med Res Opin 2007; 23(1): 175–84PubMedCrossRefGoogle Scholar
  14. 14.
    Lewis-Fernandez R, Blanco C, Mallinckrodt CH, et al. Duloxetine in the treatment of major depressive disorder: comparisons of safety and efficacy in US. Hispanic and majority Caucasian patients. J Clin Psychiatry 2006; 67(9): 1379–90PubMedCrossRefGoogle Scholar
  15. 15.
    Lobo ED, Loghin C, Knadler MP, et al. Pharmacokinetics of duloxetine in breast milk and plasma of healthy postpartum women. Clin Pharmacokinet 2008; 47(2): 103–9PubMedCrossRefGoogle Scholar
  16. 16.
    Suri A, Reddy S, Gonzales C, et al. Duloxetine pharmacokinetics in cirrhotics compared with healthy subjects. Int J Clin Pharmacol Ther 2005; 43(2): 78–84PubMedGoogle Scholar
  17. 17.
    Cymbalta package insert. Indianapolis (IN): Eli Lilly Pharmaceuticals, 2009Google Scholar
  18. 18.
    Satonin DK, McCulloch JD, Kuo F, et al. Development and validation of a liquid chromatography-tandem mass spectrometric method for the determination of the major metabolites of duloxetine in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2007; 852(1–2): 582–9PubMedGoogle Scholar
  19. 19.
    Beal SL, Sheiner LB. NONMEM users guide—part VII** conditional estimation methods. San Francisco (CA): Regents of the University of California, 1992: 1–15Google Scholar
  20. 20.
    Maderma JW, Verotta D, Sheiner LB. Building population pharmacokinetic-pharmacodynamic models. J Pharmacokinet Biopharm 1992; 20(5): 511–27Google Scholar
  21. 21.
    Relling MV, Lin JS, Ayers GD, et al. Racial and gender differences in N-acetyltransferase, xanthine oxidase, and CYP1A2 activities. Clin Pharmacol Ther 1992; 52(6): 643–58PubMedCrossRefGoogle Scholar
  22. 22.
    Schrenk D, Brockmeier D, Morike K, et al. A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers. Eur J Clin Pharmacol 1998; 53(5): 361–7PubMedCrossRefGoogle Scholar
  23. 23.
    Dawling S, Crome P. Clinical pharmacokinetic considerations in the elderly: an update. Clin Pharmacokinet 1989; 17(4): 236–63PubMedCrossRefGoogle Scholar
  24. 24.
    Hammerlein A, Derendorf H, Lowenthal DT. Pharmacokinetic and pharmacodynamic changes in the elderly: clinical implications. Clin Pharmacokinet 1998; 35(1): 49–64PubMedCrossRefGoogle Scholar
  25. 25.
    Kinirons MT, Crome P. Clinical pharmacokinetic considerations in the elderly: an update. Clin Pharmacokinet 1997; 33(4): 302–12PubMedCrossRefGoogle Scholar
  26. 26.
    Rowland M, Tozer TN. Clinical pharmacokinetics: concepts and applications. 3rd ed. Philadelphia (PA): Lippincott Williams & Wilkins, 1995Google Scholar
  27. 27.
    Bailey RK, Mallinckrodt CH, Wohlreich MM, et al. Duloxetine in the treatment of major depressive disorder: comparisons of safety and efficacy. J Natl Med Assoc 2006; 98(3): 437–47PubMedGoogle Scholar
  28. 28.
    Viktrup L, Yalcin I. Duloxetine treatment of stress urinary incontinence in women: effects of demographics, obesity, chronic lung disease, hypoestrogenism, diabetes mellitus, and depression on efficacy. Eur J Obstet Gynecol Reprod Biol 2007; 133(1): 105–13PubMedCrossRefGoogle Scholar
  29. 29.
    Wohlreich MM, Wiltse CG, Desaiah D, et al. Duloxetine in practice-based clinical settings: assessing effects on the emotional and physical symptoms of depression in an open-label, multicenter study. Prim Care Companion J Clin Psychiatry 2007; 9(4): 271–9PubMedCrossRefGoogle Scholar
  30. 30.
    Ziegler D, Pritchett YL, Wang F, et al. Impact of disease characteristics on the efficacy of duloxetine in diabetic peripheral neuropathic pain. Diabetes Care 2007; 30(3): 664–9PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  • Evelyn D. Lobo
    • 1
  • Tonya Quinlan
    • 1
  • Lisa O’Brien
    • 1
  • Mary Pat Knadler
    • 1
  • Michael Heathman
    • 1
  1. 1.Lilly Research LaboratoriesIndianapolisUSA
  2. 2.Eli Lilly and CompanyLilly Research Laboratories, DC 0724IndianapolisUSA

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