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.
    Full-text · Article · Dec 2014 · The International Journal of Neuropsychopharmacology
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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.
    Full-text · Article · Sep 2013 · PLoS ONE
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    • "To illustrate the importance of using consistent model assumptions across studies and analyses, we attempted a similar analysis of the human duloxetine SERT occupancy data that were reported by Takano et al. (2006). The human receptor occupancy data (Fig. 1b "
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    ABSTRACT: Translation of central nervous system receptor occupancy from animal models to humans has been elusive for many theraprutic targets. However, this may represent a valuable link to clinical efficacy of drugs acting within the brain and spinal cord. The introduction of positron emission tomography (PET) has marked a significant noninvasive advance in determination of target engagement in the central nervous system. Pharmacokinetic/ pharmacodynamic (PK/PD) modeling represents a valuable tool to translate ex vivo receptor occupancy from relevant animal models to humans. While PK properties usually are reasonably scaled across species using standard allometric principles, PD properties related to receptor occupancy are usually species-independent. The translational value and applicability of PK/PD approaches is more directly evident when comparable modeling assumptions and mathematical model structures are employed across experiments and analyses. The purpose of this letter is to review the basic principles of PK/PD analysis of receptor occupancy determined using noninvasive PET imaging, and first principles of allometric PK scaling and PD prediction based on animal data. We also provide a case study of PK/PD analysis showcasing the importance of PK/PD model assumptions in predicting receptor occupancy in humans based on data from animal models using data from the area of pain management.
    Preview · Article · Jul 2013 · Journal of Pharmacology and Experimental Therapeutics
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