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Single- and Multiple-Dose Milnacipran Pharmacokinetics in Healthy Han Chinese Volunteers

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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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References

  1. Assie MB, Charveron M, Palmier C, Puozzo C, Moret C, Briley M. Effects of prolonged administration of milnacipran, a new antidepressant, on receptors and monoamine uptake in the brain of the rat. Neuropharmacology. 1992;31(2):149–55.

    Article  CAS  PubMed  Google Scholar 

  2. Kasper S, Pail G. Milnacipran: a unique antidepressant? Neuropsychiatr Dis Treat. 2010;6(Suppl 1):23–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Saraceni MM, Venci JV, Gandhi MA. Levomilnacipran (Fetzima): a new serotonin-norepinephrine reuptake inhibitor for the treatment of major depressive disorder. J Pharm Pract. 2013;27(4):389–95.

    Article  PubMed  Google Scholar 

  4. Citrome L. Levomilnacipran for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant—what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract. 2013;67(11):1089–104.

    Article  CAS  PubMed  Google Scholar 

  5. Preskorn SH. Milnacipran: a dual norepinephrine and serotonin reuptake pump inhibitor. J Psychiatr Pract. 2004;10(2):119–26.

    Article  PubMed  Google Scholar 

  6. Pierre Fabre Medicament. Effect of F2695 on Functional Recovery After Ischemic Stroke (LIFE). Available at: https://clinicaltrials.gov/ct2/show/NCT01639014?term=3-month+treatment+with+F2695%3A+++1+studies&rank=1. Accessed 17 Aug 2015.

  7. Palmier C, Puozzo C, Lenehan T, Briley M. Monoamine uptake inhibition by plasma from healthy volunteers after single oral doses of the antidepressant milnacipran. Eur J Clin Pharmacol. 1989;37(3):235–8.

    Article  CAS  PubMed  Google Scholar 

  8. Puozzo C, Pozet N, Deprez D, Baille P, Ung HL, Zech P. Pharmacokinetics of milnacipran in renal impairment. Eur J Drug Metab Pharmacokinet. 1998;23(2):280–6.

    Article  CAS  PubMed  Google Scholar 

  9. Puozzo C, Albin H, Vincon G, Deprez D, Raymond JM, Amouretti M. Pharmacokinetics of milnacipran in liver impairment. Eur J Drug Metab Pharmacokinet. 1998;23(2):273–9.

    Article  CAS  PubMed  Google Scholar 

  10. Puozzo C, Leonard BE. Pharmacokinetics of milnacipran in comparison with other antidepressants. Int Clin Psychopharmacol. 1996;11(Suppl 4):15–27.

    Article  PubMed  Google Scholar 

  11. Puozzo C, Lens S, Reh C, Michaelis K, Rosillon D, Deroubaix X, et al. Lack of interaction of milnacipran with the cytochrome p450 isoenzymes frequently involved in the metabolism of antidepressants. Clin Pharmacokinet. 2005;44(9):977–88.

    Article  CAS  PubMed  Google Scholar 

  12. Lin Y, Anderson GD, Kantor E, Ojemann LM, Wilensky AJ. Differences in the urinary excretion of 6-beta-hydroxycortisol/cortisol between Asian and Caucasian women. J Clin Pharmacol. 1999;39(6):578–82.

    Article  CAS  PubMed  Google Scholar 

  13. Yu KS, Cho JY, Shon JH, Bae KS, Yi SY, Lim HS, et al. Ethnic differences and relationships in the oral pharmacokinetics of nifedipine and erythromycin. Clin Pharmacol Ther. 2001;70(3):228–36.

    Article  CAS  PubMed  Google Scholar 

  14. Li F, Chin C, Wangsa J, Ho J. Excretion and metabolism of milnacipran in humans after oral administration of milnacipran hydrochloride. Drug Metab Dispos. 2012;40(9):1723–35.

    Article  CAS  PubMed  Google Scholar 

  15. Higuchi H, Yoshida K, Takahashi H, Naito S, Kamata M, Ito K, et al. Milnacipran plasma levels and antidepressant response in Japanese major depressive patients. Hum Psychopharmacol. 2003;18(4):255–9.

    Article  CAS  PubMed  Google Scholar 

  16. Gandhi M, Aweeka F, Greenblatt RM, Blaschke TF. Sex differences in pharmacokinetics and pharmacodynamics. Annu Rev Pharmacol Toxicol. 2004;44:499–523.

    Article  CAS  PubMed  Google Scholar 

  17. Hunt CM, Westerkam WR, Stave GM. Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol. 1992;44(2):275–83.

    Article  CAS  PubMed  Google Scholar 

  18. Zhu B, Liu ZQ, Chen GL, Chen XP, Ou-Yang DS, Wang LS, et al. The distribution and gender difference of CYP3A activity in Chinese subjects. Br J Clin Pharmacol. 2003;55(3):264–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Caccia S. Metabolism of the newest antidepressants: comparisons with related predecessors. IDrugs. 2004;7(2):143–50.

    CAS  PubMed  Google Scholar 

  20. Caccia S. Metabolism of the newer antidepressants. An overview of the pharmacological and pharmacokinetic implications. Clin Pharmacokinet. 1998;34(4):281–302.

    Article  CAS  PubMed  Google Scholar 

  21. Brocks DR, Mehvar R. Rate and extent of drug accumulation after multiple dosing revisited. Clin Pharmacokinet. 2010;49(7):421–38.

    Article  CAS  PubMed  Google Scholar 

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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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Correspondence to Chuan-Yue Wang.

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Conflicts of interest

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.

Additional information

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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