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

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.