Abstract
Background
The pharmacokinetics of milnacipran have been studied in Caucasian subjects but not in Chinese subjects.
Methods
This single-center, open-label study evaluated the pharmacokinetics and safety of oral milnacipran administered as a randomized, three-way crossover, single-dose (25, 50 and 100 mg) and in multiple doses for 8 days (up to 100 mg/day administered as 50 mg twice daily) in Han Chinese healthy volunteers. Both the single- and multiple-dose studies included 12 different adults (six males and six females), respectively. Pharmacokinetic parameters for milnacipran were determined using WinNonlin version 6.3. The safety evaluation included adverse events (AEs) assessed by monitoring, physical examinations, vital signs, and clinical laboratory tests.
Results
Plasma concentrations of milnacipran reached a time to maximum concentration (t max) of 1.2–4.3 h after each single dose, and then declined, with a mean half-life (t ½) of 7.0–7.3 h over the dose range of 25–100 mg; the area under the curve (AUC) and maximum concentration (C max) values increased in a dose-proportional manner. After multiple doses, steady state was reached by day 4 and the accumulation was low, with an accumulation index <1.65. No significant sex differences were observed in milnacipran pharmacokinetic parameters and, additionally, no severe AEs were observed in the single- or multiple-dose studies. The most common reported AEs were nausea, vomiting, dizziness and water brash, which appears to be dose-related.
Conclusion
Milnacipran was safe and well-tolerated in healthy volunteers and displayed linear increase in the C max and AUC values at doses ranging from 25 to 100 mg once daily.
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Acknowledgments
The authors wish to thank all of the volunteers, investigators, and medical, nursing and laboratory staff who participated in this study. They would also like to thank Lorraine Maw, MA, at the Mental Health Research Center, Eastern State Hospital, Lexington, KY, USA, for editorial assistance.
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The writing of this article was completed without any external funding. The study was financed by two grants to Beijing Anding Hospital: one with Dr. Ruan as the principal investigator (the Capital Medical Research Development Fund of China (2014-2-2122), and another with Dr. Wang as the principal investigator combining two sources—Shanghai Shyndec Pharmaceutical Co., Ltd, and the Beijing Municipal Administration of Hospitals Clinical Medicine Development of special funding (ZY201403). Drs. Dong, Li, Zhai, Li and de Leon report no conflicts of interest in the last 36 months.
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C.-J. Ruan and A.-N. Li contributed equally to this paper.
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Ruan, CJ., Li, AN., Dong, F. et al. Single- and Multiple-Dose Milnacipran Pharmacokinetics in Healthy Han Chinese Volunteers. Clin Pharmacokinet 55, 889–896 (2016). https://doi.org/10.1007/s40262-015-0355-2
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DOI: https://doi.org/10.1007/s40262-015-0355-2