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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...

The objective was to describe the pharmacokinetics of vortioxetine and evaluate the effect of intrinsic and extrinsic factors in the healthy population. Data from 26 clinical pharmacology studies were pooled. A total of 21,758 vortioxetine quantifiable plasma concentrations were collected from 887 subjects with corresponding demography. The doses ranged from 2.5 to 75 mg (single dose) and 2.5–60 mg (multiple QD doses). The pharmacokinetics of vortioxetine was best characterised by a two-compartment model with first-order absorption, lag-time and linear elimination, with interindividual error terms for absorption rate constant, oral clearance and central volume of distribution. The population mean was 32.7 L/hr for oral clearance and 1.97·103 L for the central volume of distribution. The average elimination half-life was 65.8 hr. CYP2D6 inferred metabolic status (ultra, extensive, intermediate or poor metabolisers) and age on oral clearance and height on central volume of distribution were identified as statistically significant covariate–parameter relationships. For CYP2D6 poor metabolisers, CL/F was approximately 50% to that seen in CYP2D6 extensive metabolisers. The impact of height on V2/F and age on CL/F was low and not considered to be clinically relevant. The final model was found to be reliable, stable and predictive. A reliable, stable and predictive pharmacokinetic model was developed to characterise pharmacokinetics of vortioxetine in the healthy population.

Owing to the lack of biologically based clinical measures and reliable biomarkers for many indications within the CNS area, the use of imaging tools, such as ligand-based positron emission tomography (PET), has become more and more important in the development of new CNS drugs. A well-grounded and reliable relationship between the plasma concentration of the drug and the occupancy of the receptor ⁄ transporter is a powerful tool to investigate the mechanism of action of a new drug and to guide dose selection in patients.Imaging of the serotonin transporter (5-HTT) by means of either PET or single photon emission computed tomography (SPECT) is one of the most useful methods in the neuro-and psychopharmacological field. A number of different ligands have been tested and used over the past 20 years. The first radiotracer ligand to be used in human beings was the SPECT ligand [ The purpose of this study was to describe the 5-HTT human brain occupancy after Lu AA21004 administration and its relation to the plasma concentrations of Lu AA21004. Material and MethodsStudy designs. Data originate from two different open-label studies, performed at different sites (necessary because of subject recruitment) and with access to different 5-HTT ligands. In study A, PET measurements were taken on day 1 (i.e. after a single dose) and on day 9 of multiple dosing in 11 young healthy Caucasian subjects using the [ 11 C]-MADAM ligand. In study B, PET measurements were taken after 13 days of multiple dosing in 35 young healthy Caucasian or Japanese subjects with the [ 11 C]-DASB ligand. Study A investigated the 5-HTT occupancy at three dose levels of Lu AA21004 (2.5, 10 and 60 mg ⁄ day), whereas the doses in study B were 2.5, 5 and 20 mg ⁄ day. Both studies were approved by local ethics committees and were conducted in accordance with Good Clinical Practice (GCP) and the Declaration of Helsinki.