title: Pharmacokinetics and tolerability of duloxetine following oral administration to healthy Chinese subjects.
abstract: OBJECTIVE
  The objectives of the study were to characterise the pharmacokinetics and assess the tolerability of duloxetine in healthy Chinese subjects after single and multiple oral 60 mg dosing.
  
  
  METHODS
  This was a single-centre, double-blind, randomised, placebo-controlled, single-period study in healthy native Chinese subjects. A total of 32 subjects, 19 men (14 on duloxetine, 5 on placebo) and 13 women (10 on duloxetine, 3 on placebo) between the ages of 20 and 39 years, participated in the study. Duloxetine 60 mg (enteric-coated pellets in a capsule) was given orally once on day 1 and once daily on days 4 to 9. Sequential blood samples were collected over 72 hours after the dose on days 1 and 9, and a predose sample was obtained on days 7 and 8. Duloxetine concentrations in plasma were determined by a validated liquid chromatography-tandem mass spectrometry method. The tolerability evaluation included a physical examination, vital signs, adverse event monitoring and clinical laboratory evaluations.
  
  
  RESULTS
  Duloxetine disposition on oral administration is characterised by a one-compartment pharmacokinetic model. Duloxetine is well absorbed, with a median time of maximum plasma concentration at 6 and 4 hours following single and multiple dosing, respectively. At steady state, the mean apparent oral clearance (CL(ss)/F), mean apparent volume of distribution (V(ss)/F) and mean terminal elimination half-life (t((1/2))) were 86.8 L/h, 1570L and 11 hours, respectively. CL/F and V(ss)/F on single dosing were not statistically significantly different (p > 0.05) compared with multiple dosing. The linearity index, calculated as the ratio of the area under the plasma concentration-time curve (AUC) during the dosing interval tau at steady state (AUC(tau)(,ss)) to the AUC from time zero to infinity after single dosing (AUC(infinity,single dose)) was 1.15 (coefficient of variation 35.7%). The accumulation in duloxetine exposure was estimated to be 50% on multiple dosing compared with single dosing, consistent with the t((1/2)) and dosing interval (24 hours). The pharmacokinetic parameters of duloxetine in Chinese subjects were not statistically significantly different from those reported previously in Caucasian and Japanese subjects. There were no clinically significant adverse events, abnormal safety laboratory data or vital sign changes reported.
  
  
  CONCLUSIONS
  Duloxetine pharmacokinetics in healthy Chinese subjects given a 60 mg once-daily dosing regimen were well characterised and consistent with known duloxetine pharmacokinetics in healthy Caucasian and Japanese subjects. Both single dosing and multiple once-daily dosing of duloxetine 60 mg were well tolerated by healthy Chinese subjects in this study.
authors: Peking University Institute of Mental Health, Beijing, China.
authors: Si
authors: S
authors: Tianmei
authors: Mary Pat
authors: MP
authors: Knadler
authors: Ming T
authors: MT
authors: Lim
authors: Kwee Poo
authors: KP
authors: Yeo
authors: Leyan
authors: L
authors: Teng
authors: Shu
authors: S
authors: Liang
authors: Alan X
authors: AX
authors: Pan
authors: Evelyn D
authors: ED
authors: Lobo
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D002681:China; D004244:Dizziness / Q000139:chemically induced; D004311:Double-Blind Method; D000068736:Duloxetine Hydrochloride; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D009325:Nausea / Q000139:chemically induced; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D012737:Sex Factors; D013876:Thiophenes / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000068736:Duloxetine Hydrochloride; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes
references: Bioorg Med Chem Lett. 2004 Jul 5;14(13):3481-6
references: 15177457
references: Eur Neuropsychopharmacol. 2004 Dec;14(6):457-70
references: 15589385
references: Curr Pharm Des. 2005;11(12):1475-93
references: 15892657
references: Br J Clin Pharmacol. 2004 May;57(5):652-6
references: 15089819
references: Pain. 2005 Dec 15;119(1-3):5-15
references: 16298061
references: Clin Pharmacol Ther. 2003 Mar;73(3):170-7
references: 12621382
references: Br J Clin Pharmacol. 2007 Mar;63(3):310-4
references: 17380590
references: Pain Med. 2005 Sep-Oct;6(5):346-56
references: 16266355
references: Clin Ther. 2005 Aug;27(8):1126-43
references: 16199241
references: Int J Clin Pharmacol Res. 2003;23(1):31-5
references: 14621071
references: IARC Sci Publ. 1999;(148):173-95
references: 10493258
references: J Clin Pharmacol. 2000 Feb;40(2):161-7
references: 10664922
references: Clin Chim Acta. 2007 May 1;380(1-2):100-5
references: 17316589
references: Ther Drug Monit. 1996 Oct;18(5):586-91
references: 8885124
references: J Urol. 2003 Oct;170(4 Pt 1):1259-63
references: 14501737
references: Int J Neuropsychopharmacol. 1998 Dec;1(2):173-185
references: 11281961
references: Drug Metab Dispos. 2003 Sep;31(9):1142-50
references: 12920170