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.

21 Reads
    • "Although plasma concentrations of duloxetine were found to be more than 2000 ng/mL, the CSF concentration was only 15 ng/mL indicating a CSF/plasma ratio of 0.008 that seems to be extremely low. Nonetheless, by using PET imaging, it could be shown that doses of 40 mg duloxetine per day were able to attain 80% occupancy of the serotonin transporter (5-HTT), and 60 mg per day was sufficient to maintain a high level of 5-HTT occupancy (Takano et al., 2006) indicating that even relatively low doses of duloxetine are able to reach sufficient concentrations at the site of action within the brain. Duloxetine is a potent and selective inhibitor of serotonin (5- HT) and norepinephrine (NE) reuptake with weak activity on dopamine reuptake (Wong et al., 1993). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Antidepressants enter the brain to reach their site of action in a different extent. However, there has been no study to date about duloxetine's ability to enter the brain and cerebrospinal fluid. Aim of this study was to measure blood and cerebrospinal fluid concentrations of duloxetine and to account for the distribution between the two compartments. Methods: Concentrations of duloxetine were measured in blood serum and cerebrospinal fluid of 19 patients treated with daily doses of 30-120mg. Daily doses were correlated with serum and cerebrospinal fluid concentrations and serum concentrations were correlated with concentrations in cerebrospinal fluid. Results: Serum concentrations of duloxetine showed a moderate but significant correlation with the applied daily dose, r=+0.473, p=0.04. Duloxetine concentrations in the cerebrospinal fluid above the designated limit of quantification of 2.0ng/mL were only found in three of the 19 patients. Conclusions and limitations: Contrasting to own preceding studies on venlafaxine, mirtazapine and citalopram with comparably high concentrations in cerebrospinal fluid, the here presented findings indicate that duloxetine shows a very different distribution pattern. Very low concentrations in the cerebrospinal fluid may be due to the fact that the drug crosses the blood-cerebrospinal fluid barrier much worse than other antidepressants do, suggesting a low ability of duloxetine to enter the brain. Alternatively, low drug concentrations may be interpreted in a sense of a missing residence time in cerebrospinal fluid due to active transport mechanisms out of this environment either back into the bloodstream or into the brain.
    Pharmacopsychiatry 09/2015; 48(06). DOI:10.1055/s-0035-1557983 · 1.85 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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
Show more

Similar Publications