A dose-finding study of duloxetine based on serotonin transporter occupancy

Molecular Imaging Center, National Institute of Radiological Sciences, 9-1, Anagawa 4-Chome, Inage-ku, Chiba, 263-8555, Japan.
Psychopharmacology (Impact Factor: 3.88). 05/2006; 185(3):395-9. DOI: 10.1007/s00213-005-0304-0
Source: PubMed


Positron emission tomography (PET) has been utilized for determining the dosage of antipsychotic drugs. To evaluate the dosage of antidepressants such as selective serotonin reuptake inhibitors, serotonin transporter occupancy (5-HTT) is also a useful index.
We investigated the degree of 5-HTT occupancy with different doses of the antidepressant duloxetine and the time-course of 5-HTT occupancy using PET.
PET scans with [11C]DASB were performed before and after a single administration of duloxetine (5-60 mg), and three consecutive scans were performed after a single dose or repeated doses of 60 mg of duloxetine.
5-HTT occupancies by duloxetine were increased by 35.3 to 86.5% with dose and plasma concentration increments. The ED50 value of 5-HTT occupancy was 7.9 mg for dose and 3.7 ng/ml for plasma concentration. In the time-course of 5-HTT occupancy, mean occupancies were 81.8% at 6 h, 71.9% at 25 h, and 44.9% at 53 h after a single administration, and 84.3% at 6 h, 71.9% at 49 h, and 47.1% at 78 h after repeated administrations.
Based on 5-HTT occupancy, 40 mg and more of duloxetine was needed to attain 80% occupancy, and 60 mg of duloxetine could maintain a high level of 5-HTT occupancy with a once-a-day administration schedule.

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    • "The protocol was approved by the Yale University Human Investigation Committee and the Yale–New Haven Hospital Radiation Safety Committee. SERT and NET occupancy were determined using the selective radiotracers [ 11 C]-DASB (Meyer et al., 2004; Takano et al., 2006; Abanades et al., 2011; Nogami et al., 2013) and [ 11 C]-MRB. Selection of the radiotracers and the dose of TD-9855 were flexible to minimize the number of PET scans. "
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    ABSTRACT: Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of Central Nervous System (CNS) transporters. We used a translational strategy, including rodent PK/PD modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor (NSRI). TD-9855 was a potent inhibitor of NE and 5-HT uptake in vitro with an inhibitory selectivity of 4 to 10-fold for NE at human and rat transporters. TD-9855 engaged NET and SERT in rat spinal cord with a plasma EC50 of 11.7 ng/mL and 50.8 ng/mL, respectively, consistent with modest selectivity for NET in vivo. Accounting for species differences in protein binding, the projected human NET and SERT plasma EC50 values were 5.5 ng/mL and 23.9 ng/mL, respectively. A single dose, open-label PET study (4-20 mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [(11)C]-DASB for SERT and [(11)C] (S,S)-methylreboxetine (MRB) for NET. The long pharmacokinetic half-life (30 - 40h) of TD 9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC50 for NET was estimated to be 1.21 ng/mL, and at doses of greater than 4 mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20 mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35 ng/mL. These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 12/2014; 18(2). DOI:10.1093/ijnp/pyu027 · 4.01 Impact Factor
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    • "Possible discrepancies between the clinical and preclinical observations with duloxetine include dose – occupancy estimates and the technical limitations of each setting. As reported by positron emission tomography, at the therapeutic dose of 60 mg duloxetine achieves near-maximal occupancy of SERT, comparable to that observed in our current study [36]. While the absolute level of NET occupancy achieved at therapeutic doses of duloxetine has not been reported, duloxetine likely engages NET at the clinical exposures [31], [37]. "
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    ABSTRACT: Multimodal analgesia is designed to optimize pain relief by coadministering drugs with distinct mechanisms of action or by combining multiple pharmacologies within a single molecule. In clinical settings, combinations of monoamine reuptake inhibitors and opioid receptor agonists have been explored and one currently available analgesic, tapentadol, functions as both a µ-opioid receptor agonist and a norepinephrine transporter inhibitor. However, it is unclear whether the combination of selective norepinephrine reuptake inhibition and µ-receptor agonism achieves an optimal antinociceptive synergy. In this study, we assessed the pharmacodynamic interactions between morphine and monoamine reuptake inhibitors that possess different affinities and selectivities for norepinephrine and serotonin transporters. Using the rat formalin model, in conjunction with measurements of ex vivo transporter occupancy, we show that neither the norepinephrine-selective inhibitor, esreboxetine, nor the serotonin-selective reuptake inhibitor, fluoxetine, produce antinociceptive synergy with morphine. Atomoxetine, a monoamine reuptake inhibitor that achieves higher levels of norepinephrine than serotonin transporter occupancy, exhibited robust antinociceptive synergy with morphine. Similarly, a fixed-dose combination of esreboxetine and fluoxetine which achieves comparable levels of transporter occupancy potentiated the antinociceptive response to morphine. By contrast, duloxetine, a monoamine reuptake inhibitor that achieves higher serotonin than norepinephrine transporter occupancy, failed to potentiate the antinociceptive response to morphine. However, when duloxetine was coadministered with the 5-HT3 receptor antagonist, ondansetron, potentiation of the antinociceptive response to morphine was revealed. These results support the notion that inhibition of both serotonin and norepinephrine transporters is required for monoamine reuptake inhibitor and opioid-mediated antinociceptive synergy; yet, excess serotonin, acting via 5-HT3 receptors, may reduce the potential for synergistic interactions. Thus, in the rat formalin model, the balance between norepinephrine and serotonin transporter inhibition influences the degree of antinociceptive synergy observed between monoamine reuptake inhibitors and morphine.
    PLoS ONE 09/2013; 8(9):e74891. DOI:10.1371/journal.pone.0074891 · 3.23 Impact Factor
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    • "fluoxetine or paroxetine) or serotonin-noradrenaline reuptake inhibitors (e.g. duloxetine ; Meyer et al. 2004 ; Takano et al. 2006 ; Talbot & Laruelle, 2002 "
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    ABSTRACT: The therapeutic effect of current antidepressant drugs appears after several weeks of treatment and a significant number of patients do not respond to treatment. Here, we report the effects of the multi-modal antidepressant vortioxetine (Lu AA21004), a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and 5-HT transporter (SERT) inhibitor, on rat 5-HT neurotransmission. Using in vivo electrophysiological recordings in the dorsal raphe nucleus of anaesthetized rats, we assessed the acute and subchronic effects of vortioxetine and/or the selective 5-HT3 receptor agonist, SR57227 or the selective 5-HT1A receptor agonist flesinoxan, on 5-HT neuronal firing activity. Using ex-vivo autoradiography, we correlated SERT occupancy and presumed 5-HT firing activity. The selective serotonin reuptake inhibitor, fluoxetine, was used as comparator. Importantly, the recovery of 5-HT neuronal firing was achieved after 1 d with vortioxetine and 14 d with fluoxetine. SR57227 delayed this recovery. In contrast, vortioxetine failed to alter the reducing action of 3 d treatment of flesinoxan. Acute dosing of vortioxetine inhibited neuronal firing activity more potently than fluoxetine. SR57227 prevented the suppressant effect of vortioxetine, but not of fluoxetine. In contrast, flesinoxan failed to modify the suppressant effect of vortioxetine acutely administered. Differently to fluoxetine, vortioxetine suppressed neuronal firing without saturating occupancy at the SERT. Vortioxetine produced a markedly faster recovery of 5-HT neuronal firing than fluoxetine. This is at least partly due to 5-HT3 receptor antagonism of vortioxetine in association with its reduced SERT occupancy.
    The International Journal of Neuropsychopharmacology 10/2012; 16(05):1-13. DOI:10.1017/S1461145712001058 · 4.01 Impact Factor
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