Pharmacokinetics, Safety, and Tolerability of Vortioxetine Following Single- and Multiple-Dose Administration in Healthy Japanese Adults

Abstract

Three phase 1 randomized single-center studies assessed the pharmacokinetics, safety, and tolerability of vortioxetine after single- and multiple-dose administration in healthy Japanese adults. Study 1 assessed the pharmacokinetics of vortioxetine after administration of single rising doses to men and multiple doses to men and women; study 2 evaluated vortioxetine pharmacokinetics in elderly adults; and study 3 assessed food effects on vortioxetine pharmacokinetics in healthy men. The primary end points included pharmacokinetic parameters of vortioxetine and incidence of adverse events (AEs). Across all studies, 130 participants were randomized and 128 participants completed the studies. Vortioxetine was absorbed and eliminated from plasma slowly, and exposure to vortioxetine increased in an almost dose-proportional manner. No clinically significant differences in the pharmacokinetics of vortioxetine or its metabolites were observed between the sexes in young and elderly adults. Study 3 demonstrated that vortioxetine and its metabolites had similar pharmacokinetics when administered in the fasted and fed states. Importantly, vortioxetine was safe and tolerated, with incidence of AEs comparable to that of placebo. No deaths or serious AEs leading to trial discontinuation were observed. Overall, vortioxetine pharmacokinetics, safety, and tolerability in Japanese adults were comparable to reports in non-Japanese populations.

Keywords: 5-HT; antidepressant; major depressive disorder; multimodal treatment; vortioxetine.

Figure 1

Dose–exposure relationship of vortioxetine (study 1A). Analysis of vortioxetine (A) C_max and (B) AUC_0–inf exposure by dose using a power model (Y = α × DOSE^β). In this model, the exponent (β) is the slope and measure of dose proportionality, which is achieved when β = 1. AUC_0–inf, area under the plasma concentration–time curve from time 0 to infinity; C_max, maximum observed plasma concentration.

Figure 2

Vortioxetine concentration–time profiles in the elderly population. Mean plasma concentrations of vortioxetine after administration of a single 10‐mg dose to elderly men and women. One woman was excluded from the pharmacokinetic analysis set because she experienced an AE (vomiting) after study drug administration. Values represent arithmetic mean; concentrations below the limit of quantification were entered as zero and included as such in the calculation of means. Error bars represent the standard deviation of the mean. AE, adverse event.

Figure 3

Vortioxetine concentration–time profiles in the fed and fasted states (study 3). Mean plasma concentration–time profiles of vortioxetine (A) and metabolite 1 (B) after single‐dose administration of 10 mg to healthy men in the fasted and fed states. Values represent arithmetic mean; concentrations below the limit of quantification were entered as zero and included as such in the calculation of means. Error bars represent the standard deviation of the mean.