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Duloxetine

Clinical Pharmacokinetics and Drug Interactions

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Abstract

Duloxetine, a potent reuptake inhibitor of serotonin (5-HT) and norepinephrine, is effective for the treatment of major depressive disorder, diabetic neuropathic pain, stress urinary incontinence, generalized anxiety disorder and fibromyalgia. Duloxetine achieves a maximum plasma concentration (Cmax) of approximately 47ng/mL (40 mg twice-daily dosing) to 110ng/mL (80 mg twice-daily dosing) approximately 6 hours after dosing. The elimination half-life of duloxetine is approximately 10–12 hours and the volume of distribution is approximately 1640 L. The goal of this paper is to provide a review of the literature on intrinsic and extrinsic factors that may impact the pharmacokinetics of duloxetine with a focus on concomitant medications and their clinical implications. Patient demographic characteristics found to influence the pharmacokinetics of duloxetine include sex, smoking status, age, ethnicity, cytochrome P450 (CYP) 2D6 genotype, hepatic function and renal function. Of these, only impaired hepatic function or severely impaired renal function warrant specific warnings or dose recommendations. Pharmacokinetic results from drug interaction studies show that activated charcoal decreases duloxetine exposure, and that CYP1A2 inhibition increases duloxetine exposure to a clinically significant degree. Specifically, following oral administration in the presence of fluvoxamine, the area under the plasma concentration-time curve and Cmax of duloxetine significantly increased by 460% (90% CI 359, 584) and 141% (90% CI 93, 200), respectively. In addition, smoking is associated with a 30% decrease in duloxetine concentration. The exposure of duloxetine with CYP2D6 inhibitors or in CYP2D6 poor metabolizers is increased to a lesser extent than that observed with CYP1A2 inhibition and does not require a dose adjustment. In addition, duloxetine increases the exposure of drugs that are metabolized by CYP2D6, but not CYP1A2. Pharmacodynamic study results indicate that duloxetine may enhance the effects of benzodiazepines, but not alcohol or warfarin. An increase in gastric pH produced by histamine H2-receptor antagonists or antacids did not impact the absorption of duloxetine. While duloxetine is generally well tolerated, it is important to be knowledgeable about the potential for pharmacokinetic interactions between duloxetine and drugs that inhibit CYP1A2 or drugs that are metabolized by CYP2D6 enzymes.

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Acknowledgements

The authors acknowledge Ryan Wright’s contribution in providing writing support for this manuscript.

This review was funded by Eli Lilly and Company (Indianapolis, IN, USA), the manufacturer of duloxetine. All authors have read the manuscript and conflict of interest statement and approved the version submitted for publication. All authors are current or former employees of Eli Lilly and Company; Richard Bergstrom is retired from Eli Lilly and Company and now works at Butler University College of Pharmacy (Indianapolis, IN, USA). All authors are stock owners in Eli Lilly and Company and have participated in the development of duloxetine.

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Correspondence to Mary Pat Knadler.

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Knadler, M.P., Lobo, E., Chappell, J. et al. Duloxetine. Clin Pharmacokinet 50, 281–294 (2011). https://doi.org/10.2165/11539240-000000000-00000

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