title: Effects of varying degrees of renal impairment on the pharmacokinetics of duloxetine: analysis of a single-dose phase I study and pooled steady-state data from phase II/III trials.
abstract: BACKGROUND
  Duloxetine is indicated for patients with a variety of conditions, and some of these patients may have mild to moderate degrees of renal impairment. Renal impairment may affect the pharmacokinetics of a drug by causing changes in absorption, distribution, protein binding, renal excretion or nonrenal clearance. As duloxetine is highly bound to plasma proteins and its metabolites are renally excreted, it is prudent to evaluate the effect of renal insufficiency on exposure to duloxetine and its metabolites in the systemic circulation.
  
  
  OBJECTIVE
  The aim of this study was to evaluate the effects of varying degrees of renal impairment on duloxetine pharmacokinetics in a single-dose phase I study and using pooled steady-state pharmacokinetic data from phase II/III trials.
  
  
  METHODS
  In the phase I study, a single oral dose of duloxetine 60 mg was given to 12 subjects with end-stage renal disease (ESRD) and 12 matched healthy control subjects. In the phase II/III trials (n = 463 patients), duloxetine 20-60 mg was given as once- or twice-daily doses. Duloxetine and metabolite concentrations in plasma were determined using liquid chromatography with tandem mass spectrometry. Noncompartmental methods (phase I: duloxetine and its metabolites) and population modelling methods (phase II/III: duloxetine) were used to analyse the pharmacokinetic data.
  
  
  RESULTS
  The maximum plasma concentration (C(max)) and the area under the plasma concentration-time curve (AUC) of duloxetine were approximately 2-fold higher in subjects with ESRD than in healthy subjects, which appeared to reflect an increase in oral bioavailability. The C(max) and AUC of two major inactive conjugated metabolites were as much as 2- and 9-fold higher, respectively, reflecting reduced renal clearance of these metabolites. Population pharmacokinetic results indicated that mild or moderate renal impairment, assessed by creatinine clearance (CL(CR)) calculated according to the Cockcroft-Gault formula, did not have a statistically significant effect on pharmacokinetic parameters of duloxetine. Values for the apparent total body clearance of duloxetine from plasma after oral administration (CL/F) in subjects with ESRD were similar to CL/F values in patients with normal renal function or with mild or moderate renal impairment.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Eli Lilly and Company, Drug Disposition, Global Pharmacokinetic/Pharmacodynamic Trial Simulation, Indianapolis, Indiana 46285-0724, USA. loboev@lilly.com
authors.forename: Evelyn D
authors.initials: ED
authors.lastname: Lobo
authors.forename: Michael
authors.initials: M
authors.lastname: Heathman
authors.forename: Han-Yi
authors.initials: HY
authors.lastname: Kuan
authors.forename: Shobha
authors.initials: S
authors.lastname: Reddy
authors.forename: Lisa
authors.initials: L
authors.lastname: O'Brien
authors.forename: Celedon
authors.initials: C
authors.lastname: Gonzales
authors.forename: Michael
authors.initials: M
authors.lastname: Skinner
authors.forename: Mary Pat
authors.initials: MP
authors.lastname: Knadler
mesh_terms: D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D000068736:Duloxetine Hydrochloride; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D013876:Thiophenes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D013876:Thiophenes; D000068736:Duloxetine Hydrochloride
references.citation: Br J Clin Pharmacol. 2007 Mar;63(3):310-4
references.pmid: 17380590
references.citation: Eur J Clin Pharmacol. 1998 Jan;53(5):361-7
references.pmid: 9516038
references.citation: Clin Pharmacokinet. 2009;48(3):189-97
references.pmid: 19385712
references.citation: Neurology. 2006 Oct 24;67(8):1411-20
references.pmid: 17060567
references.citation: Clin Pharmacokinet. 2008;47(3):191-202
references.pmid: 18307373
references.citation: J Cardiovasc Pharmacol. 2007 Mar;49(3):146-53
references.pmid: 17414226
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Jun 1;852(1-2):582-9
references.pmid: 17350901
references.citation: BJOG. 2004 Mar;111(3):249-57
references.pmid: 14961887
references.citation: J Clin Psychiatry. 2003 Oct;64(10):1237-44
references.pmid: 14658974
references.citation: Clin Pharmacol Ther. 2003 Mar;73(3):170-7
references.pmid: 12621382
references.citation: J Pharmacol Exp Ther. 1995 Jan;272(1):177-83
references.pmid: 7815331
references.citation: Bioorg Med Chem Lett. 2004 Jul 5;14(13):3481-6
references.pmid: 15177457
references.citation: Curr Med Res Opin. 2007 Jun;23(6):1245-52
references.pmid: 17559726
references.citation: Psychopharmacol Bull. 2002 Autumn;36(4):106-32
references.pmid: 12858150
references.citation: Pain. 2005 Jul;116(1-2):109-18
references.pmid: 15927394
references.citation: J Pharmacol Exp Ther. 1996 Apr;277(1):278-86
references.pmid: 8613930
references.citation: Acta Psychiatr Scand Suppl. 1997;391:7-13
references.pmid: 9265946
references.citation: Prim Care Companion J Clin Psychiatry. 2007;9(2):100-7
references.pmid: 17607331
references.citation: Neuropsychopharmacology. 1993 Jan;8(1):23-33
references.pmid: 8424846
references.citation: J Diabetes Complications. 2009 Sep-Oct;23(5):349-59
references.pmid: 18768332
references.citation: Br J Clin Pharmacol. 2004 Jan;57(1):54-61
references.pmid: 14678340
references.citation: Drug Metab Dispos. 2003 Sep;31(9):1142-50
references.pmid: 12920170
references.citation: Am J Kidney Dis. 2001 Oct;38(4 Suppl 4):S11-7
references.pmid: 11602456
references.citation: J Clin Pharmacol. 2000 Feb;40(2):161-7
references.pmid: 10664922
references.citation: Int J Clin Pharmacol Ther. 2005 Feb;43(2):78-84
references.pmid: 15726876
references.citation: BJU Int. 2008 Jul;102(2):214-8
references.pmid: 18422764
references.citation: Pain. 2005 Dec 15;119(1-3):5-15
references.pmid: 16298061
references.citation: J Clin Psychiatry. 2002 Mar;63(3):225-31
references.pmid: 11926722
references.citation: J Palliat Med. 2006 Feb;9(1):29-40
references.pmid: 16430342
references.citation: Curr Opin Investig Drugs. 2000 Sep;1(1):116-21
references.pmid: 11249587
references.citation: Clin Pharmacol Ther. 2008 Jun;83(6):898-903
references.pmid: 18388866