1. Academic Validation
  2. Preclinical to clinical translation of CNS transporter occupancy of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor

Preclinical to clinical translation of CNS transporter occupancy of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor

  • Int J Neuropsychopharmacol. 2014 Dec 13;18(2):pyu027. doi: 10.1093/ijnp/pyu027.
Jacqueline A M Smith 1 D L Bourdet O T Daniels 2 Y-S Ding 2 J-D Gallezot 2 S Henry 2 K H S Kim 2 S Kshirsagar 2 W J Martin 2 G P Obedencio 2 E Stangeland 2 P R Tsuruda 2 W Williams 2 R E Carson 2 S T Patil 2
Affiliations

Affiliations

  • 1 Theravance Biopharma US, Inc., San Francisco, CA (Drs Smith, Bourdet, Daniels, Kim, Kshirsagar, Martin, Obedencio, Stangeland, Tsururda, Williams, and Patil); Yale School of Medicine, New Haven, CT (Drs Ding, Gallezot, Henry, Williams, and Carson). jsmith@theravance.com.
  • 2 Theravance Biopharma US, Inc., San Francisco, CA (Drs Smith, Bourdet, Daniels, Kim, Kshirsagar, Martin, Obedencio, Stangeland, Tsururda, Williams, and Patil); Yale School of Medicine, New Haven, CT (Drs Ding, Gallezot, Henry, Williams, and Carson).
Abstract

Background: Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods: We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results: TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (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 (4-20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [(11)C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [(11)C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30-40 h) 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 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35 ng/mL.

Conclusions: These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.

Keywords

PET; TD-9855; norepinephrine and serotonin transporter; pain.

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