Vortioxetine is a novel antidepressant with multimodal activity currently approved for the treatment of major depressive disorder. Vortioxetine is orally administered once daily at 5- to 20-mg doses. The pharmacokinetics of vortioxetine are linear and dose proportional, with a mean terminal half-life of approximately 66 h and steady-state plasma concentrations generally achieved within 2 weeks of dosing. The mean absolute oral bioavailability of vortioxetine is 75%. No food effect on pharmacokinetics was observed. Vortioxetine is metabolized by cytochrome P450 enzymes and subsequently by uridine diphosphate glucuronosyltransferase. The major metabolite is pharmacologically inactive, and the minor pharmacologically active metabolite is not expected to cross the blood–brain barrier, making the parent compound primarily responsible for in-vivo activity. No clinically relevant differences were observed in vortioxetine exposure by sex, age, race, body size, and renal or hepatic function. Dose adjustment is only recommended for cytochrome P450 2D6 poor metabolizers based on polymorphism of the cytochrome P450 enzymes involved. Similarly, except for bupropion, a strong cytochrome P450 2D6 inhibitor, and rifampin, a broad cytochrome P450 inducer, co-administration of other drugs evaluated did not affect the vortioxetine exposure or safety profile in any clinically meaningful way. Pharmacodynamic studies demonstrated that vortioxetine achieved high levels of serotonin transporter occupancy in relevant brain areas, affected neurotransmitter levels in the cerebrospinal fluid, and modified abnormal resting state networks in the brain over the therapeutic dose range. Overall, vortioxetine can be administered in most populations studied to date without major dose adjustments; however, dose adjustments should be considered on a patient-by-patient basis.Electronic supplementary materialThe online version of this article (10.1007/s40262-017-0612-7) contains supplementary material, which is available to authorized users.

Lu AA21004 is a novel multimodal antidepressant that is currently in phase 3 development. The objective of this report was to detail the clinical pharmacokinetics of Lu AA21004 and its major but inactive metabolite Lu AA34443 (3-methyl-4-(2-piperazine-1-yl-phenylsulfanyl)-benzoic acid) in healthy men and women aged between 18 and 53 years. Data from two single-dose and one multiple-dose study were combined; the total number of volunteers was 97 (64 men, 33 women). Blood and urine samples were collected after p.o. and i.v. administrations to determine the content of Lu AA21004 and Lu AA34443 performed with a validated method. Standard pharmacokinetic parameters were estimated with non-compartmental analysis. The absolute bioavailability was 75%. After oral administration, Lu AA21004 showed an extended absorption phase, a medium clearance and a large volume of distribution resulting in late t max values and a mean elimination half-life of 57 hr. The exposure of Lu AA21004 showed a linear relationship with dose in the dose ranges studied (up to 75-mg single dosing and 60-mg multiple dosing). After weight correction, no differences in exposure for Lu AA21004 and Lu AA34443 were observed between men and women. The renal clearance of Lu AA21004 was negligible. The major metabolite Lu AA34443 had a half-life similar to that of Lu AA21004 but a lower accumulation ratio at steady-state, indicating formation-rate-limited elimination. In conclusion, Lu AA21004 showed an extended absorption phase, a medium clearance and a large volume of distribution.is a novel multimodal antidepressant that acts as a 5-HT 3A and 5-HT 7 receptor antagonist, an agonist at the 5-HT 1A receptor, a partial agonist at the 5-HT 1B receptor and an inhibitor at the 5-HT transporter (SERT) in recombinant cells [1]. It has been shown in rat microdialysis experiments that Lu AA21004 increased extracellular 5-HT, dopamine and noradrenaline in the medial prefrontal cortex and ventral hippocampus at a low SERT occupancy (41%) and that this multimodal activity profile of Lu AA21004 is distinct from current antidepressants [2]. This has been confirmed in human beings with the positron emission tomography technique (PET), where the SERT occupancy at clinically efficacious doses of Lu AA21004 was lower than what is known to be necessary for more conventional selective serotonin reuptake inhibitors and serotonin and noradrenalin reuptake inhibitors [3].Lu AA21004 is currently in phase 3 development for the treatment of major depressive disorder (MDD). In a randomised, double-blind, placebo-controlled, active-referenced study of Lu AA21004 in patients with major depression, treatment with 5-and 10-mg Lu AA21004 for 6 weeks was well tolerated and efficacious in reducing depressive and anxious symptoms and well tolerated in patients with MDD [4].A number of clinical pharmacology studies with Lu AA21004 have been conducted, of which most have been presented as posters at congresses and conferences. An AME (absorption, metabolism and elimination) study w...

Background and ObjectiveThe identification and quantification of potential drug–drug interactions is important for avoiding or minimizing the interaction-induced adverse events associated with specific drug combinations. Clinical studies in healthy subjects were performed to evaluate potential pharmacokinetic interactions between vortioxetine (Lu AA21004) and co-administered agents, including fluconazole (cytochrome P450 [CYP] 2C9, CYP2C19 and CYP3A inhibitor), ketoconazole (CYP3A and P-glycoprotein inhibitor), rifampicin (CYP inducer), bupropion (CYP2D6 inhibitor and CYP2B6 substrate), ethinyl estradiol/levonorgestrel (CYP3A substrates) and omeprazole (CYP2C19 substrate and inhibitor).MethodsThe ratio of central values of the test treatment to the reference treatment for relevant parameters (e.g., area under the plasma concentration–time curve [AUC] and maximum plasma concentration [Cmax]) was used to assess pharmacokinetic interactions.ResultsCo-administration of vortioxetine had no effect on the AUC or Cmax of ethinyl estradiol/levonorgestrel or 5′-hydroxyomeprazole, or the AUC of bupropion; the 90 % confidence intervals for these ratios of central values were within 80–125 %. Steady-state AUC and Cmax of vortioxetine increased when co-administered with bupropion (128 and 114 %, respectively), fluconazole (46 and 15 %, respectively) and ketoconazole (30 and 26 %, respectively), and decreased by 72 and 51 %, respectively, when vortioxetine was co-administered with rifampicin. Concomitant therapy was generally well tolerated; most adverse events were mild or moderate in intensity.ConclusionDosage adjustment may be required when vortioxetine is co-administered with bupropion or rifampicin.Electronic supplementary materialThe online version of this article (doi:10.1007/s40261-013-0117-6) contains supplementary material, which is available to authorized users.

We compared the effect of vortioxetine, paroxetine and placebo after three days of dosing on sleep architecture. This was a randomised, double-blind, four-way crossover, placebo-controlled, multiple-dose study in 24 healthy young men. Subjects received 20mg vortioxetine, 40mg vortioxetine, 20mg paroxetine or placebo for three consecutive days in four different periods with at least three weeks between them. Polysomnography and blood sampling for pharmacokinetic analysis were performed on the pre-dose night and nights 1 and 3 of dosing in each period. Plasma concentrations of vortioxetine and paroxetine during the polysomnography measurement were used to estimate SERT occupancies using published relationships in healthy subjects.All three active treatments significantly increased REM onset latency and decreased time spent in REM sleep. In the pharmacokinetic/pharmacodynamics analysis significant relationships were found between REM onset latency and time spent in REM sleep and vortioxetine/paroxetine exposure. The relation between REM suppression parameters and SERT occupancy was significantly different between vortioxetine and paroxetine, despite the same SERT occupancy. This indicates that vortioxetine has a different clinical pharmacological profile from paroxetine, which may explain the differences in adverse effect profile of the two drugs, for instance the lower incidence of nausea, weight gain and sexual dysfunction with vortioxetine.

IntroductionMajor depressive disorder (MDD) is associated with a significant burden of disease in China. Awareness and better access to treatments could help alleviate the burden associated with MDD. Because variations have been observed in the pharmacokinetics (PK) of antidepressants across different races and ethnicities, evaluation of the clinical pharmacology of vortioxetine in diverse populations remains important to assess the potential need for dose adjustments.MethodsData were pooled from two phase I open-label PK studies in healthy Chinese subjects, and one phase III double-blind noninferiority study in Chinese patients with MDD to describe the PK and safety data for vortioxetine. Doses in these studies ranged from 10 mg (single dose) to 10 and 20 mg (multiple daily doses). A population PK analysis of vortioxetine in the Chinese population was conducted using nonlinear mixed-effect modeling.ResultsIn total, 186 individuals were included in the PK analysis: 79 healthy Chinese subjects and 107 Chinese patients with MDD. No clinically significant differences in the PK of vortioxetine were observed between the Chinese population and the previous data in non-Chinese populations. Because of a generally lower weight in the Chinese population compared with the non-Chinese population, exposures were 19% and 18% higher in the Chinese population than in the non-Chinese population (for maximum observed plasma concentration and area under the plasma concentration–time curve, respectively), which is not considered clinically relevant. A high prevalence of pruritus was observed in one phase I PK study (56% overall); however, this was not reflected in the phase III study in Chinese patients with MDD (0.8%).ConclusionsThe PK parameters of vortioxetine in Chinese subjects were comparable to previous data in non-Chinese subjects. Overall, no new safety concerns were raised among the Chinese population. On the basis of this analysis, the tolerability profile of vortioxetine in Chinese healthy subjects and in patients with MDD is expected to be comparable to that in the non-Chinese population.FundingH. Lundbeck A/S, Valby, Denmark.Trial RegistrationNCT01676571.Electronic supplementary materialThe online version of this article (10.1007/s12325-019-01092-4) contains supplementary material, which is available to authorized users.