Abstract
Objectives
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 60mg 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 60mg (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 (CLss/F), mean apparent volume of distribution (Vss/F) and mean terminal elimination half-life (t½) were 86.8 L/h, 1570L and 11 hours, respectively. CL/F and Vss/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 τ at steady state (AUCτ,ss) to the AUC from time zero to infinity after single dosing (AUC∞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 t½ 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.
Conclusion
Duloxetine pharmacokinetics in healthy Chinese subjects given a 60mg 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 60mg were well tolerated by healthy Chinese subjects in this study.
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Acknowledgements
The authors thank the subjects for their participation in the study and Richard F. Bergstrom, PhD, and Stephen Wise, MD, for their valuable guidance on the study design.
This study was presented in part at the American Association of Pharmaceutical Scientists Annual Meeting in San Antonio, TX, USA, October 2006. The work was funded by Eli Lilly and Company. All of the authors, except for Shu Liang, MD, Professor of Psychiatry, and Si Tianmei, PhD, are employees of Eli Lilly and Company. Dr Liang was the primary investigator and Dr Tianmei was the co-investigator for the study. Drs Liang and Tianmei have no conflicts of interest that are directly relevant to the content of this study.
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Tianmei, S., Knadler, M.P., Lim, M.T. et al. Pharmacokinetics and Tolerability of Duloxetine following Oral Administration to Healthy Chinese Subjects. Clin Pharmacokinet 46, 767–775 (2007). https://doi.org/10.2165/00003088-200746090-00004
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DOI: https://doi.org/10.2165/00003088-200746090-00004