Characterising the plasma-target occupancy relationship of the neurokinin antagonist GSK1144814 with PET

Khanum Ridler; Roger N. Gunn; Graham E. Searle; Julien Barletta; Jan Passchier; Luanna Dixson; William A. Hallett; Sharon Ashworth; Frank A. Gray; Clare Burgess; Italo Poggesi; Jonathan N. Bullman; Emiliangelo Ratti; Marc A. Laruelle; Eugenii A. Rabiner

doi:10.1177/0269881113517953

Characterising the plasma-target occupancy relationship of the neurokinin antagonist GSK1144814 with PET

Khanum Ridler, Roger N. Gunn, Graham E. Searle, Julien Barletta, Jan Passchier, Luanna Dixson, William A. Hallett, Sharon Ashworth, Frank A. Gray, Clare Burgess, Italo Poggesi, Jonathan N. Bullman, Emiliangelo Ratti, Marc A. Laruelle, Eugenii A. Rabiner^*

^*Corresponding author for this work

NIHR Maudsley Biomedical Research Centre (BRC)

Research output: Contribution to journal › Article › peer-review

19 Citations (Scopus)

Abstract

GSK1144814 is a potent, insurmountable antagonist at human NK1 and NK3 receptors. Understanding the relationship between plasma pharmacokinetics and receptor occupancy in the human brain, was crucial for dose selection in future clinical studies. GSK1144814 occupancy data were acquired in parallel with the first-time-in-human safety and tolerability study. [C-11]GR-205171 a selective NK1 receptor PET ligand was used to estimate NK1 occupancy at several time-points following single dose administration of GSK1144814. The time-plasma concentration-occupancy relationship post-single dose administration was assessed, and used to predict the plasma concentration-occupancy relationship following repeat dose administration. Repeat dose predictions were tested in a subsequent cohort of subjects examined following approximately 7 and 14 days dosing with GSK1144814. GSK1144814 was shown to demonstrate a dose-dependent occupancy of the NK1 receptor with an estimated in vivo EC50 ~0.9 ng/mL in the human brain. A direct relationship was seen between the GSK1144814 plasma concentration and its occupancy of the brain NK1 receptor, indicating that in future clinical trials the occupancy of brain receptors can be accurately inferred from the measured plasma concentration. Our data provided support for the further progression of this compound and have optimised the likely therapeutic dose range.

Original language	English
Pages (from-to)	244-253
Number of pages	10
Journal	Journal of Psychopharmacology
Volume	28
Issue number	3
DOIs	https://doi.org/10.1177/0269881113517953
Publication status	Published - Mar 2014

Keywords

PET
neurokinin
Pharmacology
NK1 RECEPTOR
HIGH-AFFINITY
GR205171
EFFICACY
BINDING
HUMANS

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1177/0269881113517953

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Ridler, K., Gunn, R. N., Searle, G. E., Barletta, J., Passchier, J., Dixson, L., Hallett, W. A., Ashworth, S., Gray, F. A., Burgess, C., Poggesi, I., Bullman, J. N., Ratti, E., Laruelle, M. A., & Rabiner, E. A. (2014). Characterising the plasma-target occupancy relationship of the neurokinin antagonist GSK1144814 with PET. Journal of Psychopharmacology, 28(3), 244-253. https://doi.org/10.1177/0269881113517953

@article{394d1d4547804aeca0825c9b5673ee86,

title = "Characterising the plasma-target occupancy relationship of the neurokinin antagonist GSK1144814 with PET",

abstract = "GSK1144814 is a potent, insurmountable antagonist at human NK1 and NK3 receptors. Understanding the relationship between plasma pharmacokinetics and receptor occupancy in the human brain, was crucial for dose selection in future clinical studies. GSK1144814 occupancy data were acquired in parallel with the first-time-in-human safety and tolerability study. [C-11]GR-205171 a selective NK1 receptor PET ligand was used to estimate NK1 occupancy at several time-points following single dose administration of GSK1144814. The time-plasma concentration-occupancy relationship post-single dose administration was assessed, and used to predict the plasma concentration-occupancy relationship following repeat dose administration. Repeat dose predictions were tested in a subsequent cohort of subjects examined following approximately 7 and 14 days dosing with GSK1144814. GSK1144814 was shown to demonstrate a dose-dependent occupancy of the NK1 receptor with an estimated in vivo EC50 ~0.9 ng/mL in the human brain. A direct relationship was seen between the GSK1144814 plasma concentration and its occupancy of the brain NK1 receptor, indicating that in future clinical trials the occupancy of brain receptors can be accurately inferred from the measured plasma concentration. Our data provided support for the further progression of this compound and have optimised the likely therapeutic dose range.",

keywords = "PET, neurokinin, Pharmacology, NK1 RECEPTOR, HIGH-AFFINITY, GR205171, EFFICACY, BINDING, HUMANS",

author = "Khanum Ridler and Gunn, {Roger N.} and Searle, {Graham E.} and Julien Barletta and Jan Passchier and Luanna Dixson and Hallett, {William A.} and Sharon Ashworth and Gray, {Frank A.} and Clare Burgess and Italo Poggesi and Bullman, {Jonathan N.} and Emiliangelo Ratti and Laruelle, {Marc A.} and Rabiner, {Eugenii A.}",

year = "2014",

month = mar,

doi = "10.1177/0269881113517953",

language = "English",

volume = "28",

pages = "244--253",

journal = "Journal of Psychopharmacology",

issn = "0269-8811",

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Ridler, K, Gunn, RN, Searle, GE, Barletta, J, Passchier, J, Dixson, L, Hallett, WA, Ashworth, S, Gray, FA, Burgess, C, Poggesi, I, Bullman, JN, Ratti, E, Laruelle, MA & Rabiner, EA 2014, 'Characterising the plasma-target occupancy relationship of the neurokinin antagonist GSK1144814 with PET', Journal of Psychopharmacology, vol. 28, no. 3, pp. 244-253. https://doi.org/10.1177/0269881113517953

TY - JOUR

T1 - Characterising the plasma-target occupancy relationship of the neurokinin antagonist GSK1144814 with PET

AU - Ridler, Khanum

AU - Gunn, Roger N.

AU - Searle, Graham E.

AU - Barletta, Julien

AU - Passchier, Jan

AU - Dixson, Luanna

AU - Hallett, William A.

AU - Ashworth, Sharon

AU - Gray, Frank A.

AU - Burgess, Clare

AU - Poggesi, Italo

AU - Bullman, Jonathan N.

AU - Ratti, Emiliangelo

AU - Laruelle, Marc A.

AU - Rabiner, Eugenii A.

PY - 2014/3

Y1 - 2014/3

N2 - GSK1144814 is a potent, insurmountable antagonist at human NK1 and NK3 receptors. Understanding the relationship between plasma pharmacokinetics and receptor occupancy in the human brain, was crucial for dose selection in future clinical studies. GSK1144814 occupancy data were acquired in parallel with the first-time-in-human safety and tolerability study. [C-11]GR-205171 a selective NK1 receptor PET ligand was used to estimate NK1 occupancy at several time-points following single dose administration of GSK1144814. The time-plasma concentration-occupancy relationship post-single dose administration was assessed, and used to predict the plasma concentration-occupancy relationship following repeat dose administration. Repeat dose predictions were tested in a subsequent cohort of subjects examined following approximately 7 and 14 days dosing with GSK1144814. GSK1144814 was shown to demonstrate a dose-dependent occupancy of the NK1 receptor with an estimated in vivo EC50 ~0.9 ng/mL in the human brain. A direct relationship was seen between the GSK1144814 plasma concentration and its occupancy of the brain NK1 receptor, indicating that in future clinical trials the occupancy of brain receptors can be accurately inferred from the measured plasma concentration. Our data provided support for the further progression of this compound and have optimised the likely therapeutic dose range.

AB - GSK1144814 is a potent, insurmountable antagonist at human NK1 and NK3 receptors. Understanding the relationship between plasma pharmacokinetics and receptor occupancy in the human brain, was crucial for dose selection in future clinical studies. GSK1144814 occupancy data were acquired in parallel with the first-time-in-human safety and tolerability study. [C-11]GR-205171 a selective NK1 receptor PET ligand was used to estimate NK1 occupancy at several time-points following single dose administration of GSK1144814. The time-plasma concentration-occupancy relationship post-single dose administration was assessed, and used to predict the plasma concentration-occupancy relationship following repeat dose administration. Repeat dose predictions were tested in a subsequent cohort of subjects examined following approximately 7 and 14 days dosing with GSK1144814. GSK1144814 was shown to demonstrate a dose-dependent occupancy of the NK1 receptor with an estimated in vivo EC50 ~0.9 ng/mL in the human brain. A direct relationship was seen between the GSK1144814 plasma concentration and its occupancy of the brain NK1 receptor, indicating that in future clinical trials the occupancy of brain receptors can be accurately inferred from the measured plasma concentration. Our data provided support for the further progression of this compound and have optimised the likely therapeutic dose range.

KW - PET

KW - neurokinin

KW - Pharmacology

KW - NK1 RECEPTOR

KW - HIGH-AFFINITY

KW - GR205171

KW - EFFICACY

KW - BINDING

KW - HUMANS

U2 - 10.1177/0269881113517953

DO - 10.1177/0269881113517953

M3 - Article

SN - 0269-8811

VL - 28

SP - 244

EP - 253

JO - Journal of Psychopharmacology

JF - Journal of Psychopharmacology

IS - 3

ER -

Characterising the plasma-target occupancy relationship of the neurokinin antagonist GSK1144814 with PET

Abstract

Keywords

UN SDGs

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