Lu AA21004 Research Articles

The Clinical Pharmacokinetics of Lu AA21004 and its Major Metabolite in Healthy Young Volunteers

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 53years. 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 57hr. 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.

Identification of the Cytochrome P450 and Other Enzymes Involved in the In Vitro Oxidative Metabolism of a Novel Antidepressant, Lu AA21004

1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine (Lu AA21004) is a novel antidepressant that is currently in late-stage clinical development for major depressive disorder. In the present study, the metabolism of Lu AA21004 was investigated using human liver microsomes (HLM), human liver S9 fraction, and recombinant enzymes. Lu AA21004 was found in vitro to be oxidized to a 4-hydroxy-phenyl metabolite, a sulfoxide, an N-hydroxylated piperazine, and a benzylic alcohol, which was further oxidized to the corresponding benzoic acid [3-methyl-4-(2-piperazin-1-yl-phenysulfanyl)-benzoic acid (Lu AA34443)]. The formation of the 4-hydroxy-phenyl metabolite was catalyzed by CYP2D6 with some contribution from CYP2C9, whereas the formation of the sulfoxide was mediated by CYP3A4/5 and CYP2A6. CYP2C9 and CYP2C19 were the primary enzymes responsible for formation of the N-hydroxylated metabolite. The benzylic alcohol was formed by CYP2D6 only. The oxidation of the benzylic alcohol to the corresponding benzoic acid of Lu AA21004 was catalyzed by alcohol dehydrogenase and aldehyde dehydrogenase, with some contribution from aldehyde oxidase. CYP2D6 was also capable of catalyzing the formation of the benzoic acid of Lu AA21004; however, its overall contribution to this pathway was negligible. Enzyme kinetic parameters revealed that the rate-limiting step in the formation of the benzoic acid from Lu AA21004 is the formation of the corresponding alcohol. Thus, the intrinsic clearance (V(max)/K(m)) in HLM for metabolism of Lu AA21004 to the benzylic alcohol was 1.13 × 10(-6) l · min(-1) · mg(-1), whereas the subsequent metabolism of the benzylic alcohol to the benzoic acid of Lu AA21004 is characterized by an intrinsic clearance (V(max)/K(m)) in S9 fraction of 922 × 10(-6) l · min(-1) · mg(-1).

A randomized clinical study of Lu AA21004 in the prevention of relapse in patients with major depressive disorder

The efficacy and tolerability of Lu AA21004 in the prevention of relapse of major depressive disorder (MDD) in patients in remission after acute treatment was evaluated. Patients (n=639) aged 18-75 years with a primary diagnosis of MDD with a current major depressive episode (MDE) ≥4 weeks' duration, at least one prior MDE and a MADRS total score ≥26 received 12-week, open-label Lu AA21004 at 5 or 10mg/day. Patients in remission (MADRS ≤10) at both weeks 10 and 12 were assigned to double-blind treatment with either placebo or Lu AA21004 (fixed dose from Week 8).Patients (n=396) were treated, after random assignment to placebo (n=192) or Lu AA21004 (n=204). The primary analysis of time to relapse (full-analysis set, Cox proportional hazard model) showed a statistically significant difference in favour of Lu AA21004 versus placebo with a hazard ratio of 2.01 (95% confidence interval: 1.26-3.21; p=0.0035). The proportion of patients who relapsed was 13% in the Lu AA21004 group (n=27) and 26% in the placebo group (n=50). The withdrawal rates due to adverse events were 8% (open-label), and 3% (placebo) and 8% (Lu AA21004) (double-blind). Thus, Lu AA21004 was effective in preventing relapse of MDD and was well tolerated as maintenance treatment.

A randomised, double-blind, placebo controlled, duloxetine-referenced, fixed-dose study of three dosages of Lu AA21004 in acute treatment of major depressive disorder (MDD)

The efficacy, safety, and tolerability of Lu AA21004 versus placebo, using duloxetine as active reference, in patients with DSM-IV-TR diagnosed major depressive disorder (MDD) were evaluated in this 8-week, multi-site study. Patients (n=766) had a baseline Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≥26 and were randomly assigned (1:1:1:1:1) to 2.5, 5 or 10mg Lu AA21004, placebo, or 60mg duloxetine. The 5mg and 10mg doses of Lu AA21004 were tested separately versus placebo at p≤0.025 in a pre-specified order. In the pre-defined primary efficacy analysis [mean change from baseline in MADRS total score at Week 8, full analysis set, ANCOVA, last observation carried forward (LOCF)], the differences to placebo (n=145) of −1.7 (Lu AA21004 5mg, n=155) and −1.5 points (Lu AA21004 10mg, n=151) were not statistically significant; nor were those for Lu AA21004 2.5mg (−1.4 points, n=155) or duloxetine (−2.0 points, n=149). Using mixed model, repeated measures (MMRM) analyses of the primary endpoint and most secondary endpoints were supportive of likely efficacy for Lu AA21004 5mg and 10mg and duloxetine. Treatment-emergent adverse events led to the withdrawal of 72 patients: 8% (placebo), 12% (duloxetine), and 6%, 11% and 9% in the Lu AA21004 groups (2.5mg, 5mg and 10mg, respectively). The most common adverse events were nausea, headache, dizziness, and dry mouth. No clinically relevant changes were seen in vital signs, weight, ECG, or laboratory results. In summary, none of the active treatment groups, including duloxetine, separated from placebo in the primary analysis in this 'failed' study. Findings on secondary outcome measures, using MMRM instead of LOCF, were supportive of likely efficacy for Lu AA21004 5mg and 10mg and duloxetine. Lu AA21004 (2.5, 5 and 10mg) was well tolerated.

Pharmacological Effects of Lu AA21004: A Novel Multimodal Compound for the Treatment of Major Depressive Disorder

1-[2-(2,4-Dimethylphenyl-sulfanyl)-phenyl]-piperazine (Lu AA21004) is a human (h) serotonin (5-HT)(3A) receptor antagonist (K(i) = 3.7 nM), h5-HT(7) receptor antagonist (K(i) = 19 nM), h5-HT(1B) receptor partial agonist (K(i) = 33 nM), h5-HT(1A) receptor agonist (K(i) = 15 nM), and a human 5-HT transporter (SERT) inhibitor (K(i) = 1.6 nM) (J Med Chem 54:3206-3221, 2011). Here, we confirm that Lu AA21004 is a partial h5-HT(1B) receptor agonist [EC(50) = 460 nM, intrinsic activity = 22%] using a whole-cell cAMP-based assay and demonstrate that Lu AA21004 is a rat (r) 5-HT(7) receptor antagonist (K(i) = 200 nM and IC(50) = 2080 nM). In vivo, Lu AA21004 occupies the r5-HT(1B) receptor and rSERT (ED(50) = 3.2 and 0.4 mg/kg, respectively) after subcutaneous administration and is a 5-HT(3) receptor antagonist in the Bezold-Jarisch reflex assay (ED(50) = 0.11 mg/kg s.c.). In rat microdialysis experiments, Lu AA21004 (2.5-10.0 mg/kg s.c.) increased extracellular 5-HT, dopamine, and noradrenaline in the medial prefrontal cortex and ventral hippocampus. Lu AA21004 (5 mg/kg per day for 3 days; minipump subcutaneously), corresponding to 41% rSERT occupancy, significantly increased extracellular 5-HT in the ventral hippocampus. Furthermore, the 5-HT(3) receptor antagonist, ondansetron, potentiated the increase in extracellular levels of 5-HT induced by citalopram. Lu AA21004 has antidepressant- and anxiolytic-like effects in the rat forced swim (Flinders Sensitive Line) and social interaction and conditioned fear tests (minimal effective doses: 7.8, 2.0, and 3.9 mg/kg). In conclusion, Lu AA21004 mediates its pharmacological effects via two pharmacological modalities: SERT inhibition and 5-HT receptor modulation. In vivo, this results in enhanced release of several neurotransmitters and antidepressant- and anxiolytic-like profiles at doses for which targets in addition to the SERT are occupied. The multimodal activity profile of Lu AA21004 is distinct from that of current antidepressants.

Occupancy of the Serotonin Transporter after Administration of Lu AA21004 and its Relation to Plasma Concentration in Healthy Subjects

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

Biosynthesis and Identification of an N-Oxide/N-Glucuronide Metabolite and First Synthesis of an N-O-Glucuronide Metabolite of Lu AA21004

This article describes the biosynthesis and identification of a new class of metabolites, a piperazine N-oxide/N-glucuronide metabolite 4-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-1-β-D-glucuronic acid-piperazine 1-oxide (4). The metabolite was found in urine and plasma from humans and animals dosed with 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (Lu AA21004, 1), as a novel multimodal antidepressant under development for treatment of depression. Human liver microsomes in combination with uridine 5'-diphosphoglucuronic acid were used as an in vitro system to generate enough material of 4 to perform one- and two-dimensional (1)H and (13)C NMR experiments for structure elucidation. Based on rotating frame Overhauser enhancement spectroscopy NMR experiments, the distance correlation between a piperazine proton and the anomeric proton of the glucuronic acid moiety is of a magnitude similar to that of the H-3' and H-5' protons and can only be explained by proximity in space and the postulated structure (4). The structural analog, the N-O-glucuronic acid conjugate 6-{4-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazin-1-yloxy}-1-β-D-glucuronic acid (3) was also observed in biological samples from humans and animals and the first organic synthesis and structural identification of this metabolite is also reported. Treatment of the glucuronide metabolites 3 and 4 with β-glucuronidase gave mainly the expected hydrolysis product, the hydroxyl amine 4-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazin-1-ol (2).

P.2.c.024 A double-blind, randomised, placebocontrolled, relapse-prevention study with Lu AA21004 in patients with major depressive disorder

P.2.c.024 A double-blind, randomised, placebocontrolled, relapse-prevention study with Lu AA21004 in patients with major depressive disorder

P.2.b.016 Preclinical characterisation of the novel antidepressant Lu AA21004: key role for the 5-HT3 receptors blockade

P.2.b.016 Preclinical characterisation of the novel antidepressant Lu AA21004: key role for the 5-HT3 receptors blockade

P.2.d.011 Lu AA21004, a novel antidepressant, modulates neurotransmitter levels and theta oscillations, and exerts pro-cognitive effects in rats

P.2.d.011 Lu AA21004, a novel antidepressant, modulates neurotransmitter levels and theta oscillations, and exerts pro-cognitive effects in rats

P.2.c.013 A randomised, double-blind, placebo controlled, duloxetine-referenced, fixed-dose study of three dosages of Lu AA21004 in MDD treatment

While patients with late-life depression (LLD) often exhibit microstructural white matter alterations that can be identified with diffusion tensor imaging (DTI), there is a dearth of information concerning the links between DTI findings and specific cognitive performance, as well as between DTI measures and antidepressant treatment outcomes.Neuroimaging and cognitive tests were conducted at baseline in 71 older adults participating in a larger, 8-week duration antidepressant randomized controlled trial. Correlations between DTI measures of white matter integrity evaluated with tract-based spatial statistics, baseline neurocognitive performance, and prospective antidepressant treatment outcome were evaluated.Fractional anisotropy (FA), an index of white matter integrity, was significantly positively associated with better cognitive function as measured by the Initiation/Perseveration subscale of the Dementia Rating Scale in the bilateral superior longitudinal fasciculus (SLF), bilateral SLF-temporal, and right corticospinal tract (CST). An exploratory analysis limited to these tracts revealed that increased FA in the right CST, right SLF, and right SLF-temporal tracts was correlated with a greater decrease in depressive symptoms. Increased FA in the right CST predicted a greater chance of remission, while increased FA in the right CST and the right SLF predicted a greater chance of treatment response.In late-life depression LLD subjects, white matter integrity was positively associated with executive function in white matter tracts which act as key connecting structures underlying the cognitive control network. These tracts may play a role as a positive prognostic factor in antidepressant treatment outcome.

P.2.d.003 Acute and subchronic Lu AA21004 induces monoamine release through a mechanism involving multiple serotonergic receptors

The microdialysis technique for acetylcholine (ACh) first became possible when sensitive and specific assays for ACh (pmol/sample range) were developed [G. Damsma, B.H.C. Westerink, P. de Boer, J.B. de Vries, A.S. Horn, Determination of basal acetylcholine release in freely moving rats by transstriatal dialysis coupled to on-line HPLC analysis: pharmacological aspects, Life Sci. 43 (1988) 1161–1168; G. Damsma, B.H.C. Westerink, A. Imperato, H. Rollema, J.B. de Vries, A.S. Horn, Automated brain dialysis of acetylcholine in freely moving rats: detection of basal acetylcholine, Life Sci. 41 (1987) 873–876; P.E. Potter, J.L. Meek, N.H. Neff, Acetylcholine and choline in neural tissue measured by HPLC with electrochemical detection, J. Neurochem. 41 (1983) 188–194; B.H.C. Westerink, G. Damsma, Determination of acetylcholine in microdialysates by HPLC and electrochemical detection, Neurosci. Protocols 20 (1993) 1–9.]. In the present protocol, the microdialysis technique was used to correlate ACh release with the recovery of the ability to acquire a conditioning taste aversion (CTA), by fetal brain grafts in insular cortex (IC) lesioned rats [M.I. Miranda, A.M. Lopez-Colome, F. Bermúdez Rattoni, Recovery of conditioned taste aversion induced by fetal neocortex grafts. In vivo correlation of acetylcholine levels, Brain Res. 759 (1997) 141–148]. Three groups of IC lesioned rats showing disrupted CTA received cell suspension grafts of fetal tissue dissected from either the IC or occipital cortex (OC) of 16-day-old rat fetuses. One of the groups of IC-grafted animals was tested after 15 days post-graft; the other groups, IC- and OC-grafted animals, were tested after a recovery time of 45 days, as well as the groups of lesioned and unoperated animals used as control. After the CTA test, guide cannulas were stereotaxically implanted into the IC of all groups. Two days later, microdialysis was performed to determine the extracellular levels of ACh inside the graft. The dialysates were analyzed by high-performance liquid chromatography and electrochemical detection. The ACh was converted by the enzyme acetylcholinesterase to choline, and subsequently by choline oxidase to hydrogen peroxide [J.L. Meek, C. Eva, Enzymes adsorbed on an ion exchanger as a post-column reactor: application to acetylcholine measurement, J. Chromatogr. 317 (1984) 343–347.]. The reactor with these enzymes was placed between the analytical column and the electrochemical detector. The hydrogen peroxide produced was detected with a platinum electrode, and choline was determined concurrently. We believe that the application of free-moving microdialysis as a method to measure the cholinergic levels inside the transplant at two post-graft periods, is a good, direct technique to correlate the effects of ACh levels from the fetal grafts in lesioned rats.Theme: Neural basis of behaviorTopics: Learning and memory: physiology

P.2.b.018 Progesterone withdrawal models of depression in rats: behavioural characterisation and efficacy of Lu AA21004 and fluoxetine

P.2.b.018 Progesterone withdrawal models of depression in rats: behavioural characterisation and efficacy of Lu AA21004 and fluoxetine

P.2.c.018 Efficacy and tolerability of multiple doses of LU AA21004 in an 8-week trial of adults with major depressive disorder

P.2.c.018 Efficacy and tolerability of multiple doses of LU AA21004 in an 8-week trial of adults with major depressive disorder

P.2.d.006 The novel antidepressant Lu AA21004 exerts its multi-modal activity through serotonergic targets

P.2.d.006 The novel antidepressant Lu AA21004 exerts its multi-modal activity through serotonergic targets

A double-blind, randomized, placebo-controlled, active reference study of Lu AA21004 in patients with major depressive disorder

The efficacy, safety, and tolerability of Lu AA21004 vs. placebo using venlafaxine XR as active reference in patients with DSM-IV-TR major depressive disorder (MDD) were evaluated. Lu AA21004 is a novel antidepressant that is a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1A receptor agonist, 5-HT1B receptor partial agonist and inhibitor of the 5-HT transporter in recombinant cell lines. In this 6-wk, multi-site study, 429 patients were randomly assigned (1:1:1:1) to 5 or 10 mg Lu AA21004, placebo or 225 mg venlafaxine XR. All patients had a baseline Montgomery–Åsberg Depression Rating Scale (MADRS) total score ⩾30. The primary efficacy analysis was based on the MADRS total score adjusting for multiplicity using a hierarchical testing procedure starting with the highest dose vs. placebo. Lu AA21004 was statistically significantly superior to placebo (n=105) in mean change from baseline in MADRS total score at week 6 (p<0.0001, last observation carried forward), with a mean treatment difference vs. placebo of 5.9 (5 mg, n=108), and 5.7 (10 mg, n=100) points. Venlafaxine XR (n=112) was also significantly superior to placebo at week 6 (p<0.0001). In total, 30 patients withdrew due to adverse events (AEs) – placebo: four (4%); 5 mg Lu AA21004: three (3%); 10 mg Lu AA21004: seven (7%); and venlafaxine: 16 (14%). The most common AEs were nausea, headache, hyperhidrosis, and dry mouth. No clinically relevant changes over time were seen in the clinical laboratory results, vital signs, weight, or ECG parameters. In this study, treatment with 5 mg and 10 mg Lu AA21004 for 6 wk was efficacious and well tolerated in patients with MDD.

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Discovery of 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): A Novel Multimodal Compound for the Treatment of Major Depressive Disorder

The synthesis and structure-activity relationship of a novel series of compounds with combined effects on 5-HT(3A) and 5-HT(1A) receptors and on the serotonin (5-HT) transporter (SERT) are described. Compound 5m (Lu AA21004) was the lead compound, displaying high affinity for recombinant human 5-HT(1A) (K(i) = 15 nM), 5-HT(1B) (K(i) = 33 nM), 5-HT(3A) (K(i) = 3.7 nM), 5-HT(7) (K(i) = 19 nM), and noradrenergic β(1) (K(i) = 46 nM) receptors, and SERT (K(i) = 1.6 nM). Compound 5m displayed antagonistic properties at 5-HT(3A) and 5-HT(7) receptors, partial agonist properties at 5-HT(1B) receptors, agonistic properties at 5-HT(1A) receptors, and potent inhibition of SERT. In conscious rats, 5m significantly increased extracellular 5-HT levels in the brain after acute and 3 days of treatment. Following the 3-day treatment (5 or 10 (mg/kg)/day) SERT occupancies were only 43% and 57%, respectively. These characteristics indicate that 5m is a novel multimodal serotonergic compound, and 5m is currently in clinical development for major depressive disorder.

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P01-67 - 5HT1A agonist activity and the antidepressant efficacy of Lu AA21004

ObjectivesTo discuss a case study that suggests advantages for the combination of 5HT transporter inhibition plus 5HT1A receptor agonism over transporter inhibition alone.MethodsNaturalistic clinical case study.ResultsThe patient had a documented 10 year history of poor response to SSRI's including s-citalopram. There was no suggestion of placebo response in the past. He responded well to Lu AA21004 and sustained this remission over a period of 9 months. He relapsed after Lu AA21004 was ceased. He recovered and again achieved a sustained remission after being prescribed a combination of s-citalopram plus pindolol.ConclusionsThe addition of pindolol (a 5HT1A receptor partial agonist) to s-citalopram adds 5HT1A receptor agonism to the 5HT transporter inhibition of s-citalopram. This is a similar profile to Lu AA21004. It is noted that Lu AA21004 also has 5HT3 receptor antagonism which is postulated to impact more on side effect profile than antidepressant efficacy. The current case strongly suggests that (in some instances at least) the addition of 5HT1A agonism to 5HT transporter inhibition might convert non-responders to responders and thus offer clinical advantage over transporter inhibition alone.