Prediction of repeat-dose occupancy from single-dose data

characterisation of the relationship between plasma pharmacokinetics and brain target occupancy

Sergio Abanades, Jasper van der Aart, Julien A. R. Barletta, Carmine Marzano, Graham E. Searle, Cristian A. Salinas, Javaad J. Ahmad, Richard R. Reiley, Sabina Pampols-Maso, Stefano Zamuner, Vincent J. Cunningham, Eugenii A. Rabiner, Marc A. Laruelle, Roger N. Gunn

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Positron emission tomography (PET) is used in drug development to assist dose selection and to establish the relationship between blood and tissue pharmacokinetics (PKs). We present a new biomathematical approach that allows prediction of repeat-dose (RD) brain target occupancy (TO) using occupancy data obtained after administration of a single dose (SD). A PET study incorporating a sequential adaptive design was conducted in 10 healthy male adults who underwent 4 PET scans with [C-11] DASB ([C-11]N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine): 1 at baseline, 2 after 20mg SD of the 5-hydroxytryptamine transporter (5-HTT) inhibitor duloxetine, and 1 after 4 days daily administration of 20mg duloxetine. An adaptive design was used to select optimal times after SD for measurement of occupancy. Both direct and indirect PK/TO models were fitted to the SD data to characterise the model parameters and then applied to a predicted RD duloxetine plasma time course to predict the 5-HTT occupancy after RD. Repeat-dose prediction from the indirect model (OC50 = 2.62 +/- 0.93 ng/mL) was significantly better (P < 0.05) than that from the direct model (OC50 = 2.29 +/- 1.11 ng/mL). This approach increases the value of SD occupancy studies that are performed as part of first time in human drug development programmes by providing an estimate of the dose required to achieve the desired TO at RD. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 944-952; doi:10.1038/jcbfm.2010.175; published online 13 October 2010

Original languageEnglish
Pages (from-to)944-952
Number of pages9
JournalJournal of Cerebral Blood Flow and Metabolism
Volume31
Issue number3
DOIs
Publication statusPublished - Mar 2011

Keywords

  • drug occupancy
  • duloxetine
  • 5-HTT
  • mathematical modelling
  • positron emission tomography (PET)
  • positron-emission-tomography
  • serotonin transporter
  • drug development
  • in-vitro
  • PET
  • receptor
  • perspectives
  • C-11-DASB
  • design

Cite this

Prediction of repeat-dose occupancy from single-dose data : characterisation of the relationship between plasma pharmacokinetics and brain target occupancy. / Abanades, Sergio; van der Aart, Jasper; Barletta, Julien A. R.; Marzano, Carmine; Searle, Graham E.; Salinas, Cristian A.; Ahmad, Javaad J.; Reiley, Richard R.; Pampols-Maso, Sabina; Zamuner, Stefano; Cunningham, Vincent J.; Rabiner, Eugenii A.; Laruelle, Marc A.; Gunn, Roger N.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 31, No. 3, 03.2011, p. 944-952.

Research output: Contribution to journalArticle

Abanades, S, van der Aart, J, Barletta, JAR, Marzano, C, Searle, GE, Salinas, CA, Ahmad, JJ, Reiley, RR, Pampols-Maso, S, Zamuner, S, Cunningham, VJ, Rabiner, EA, Laruelle, MA & Gunn, RN 2011, 'Prediction of repeat-dose occupancy from single-dose data: characterisation of the relationship between plasma pharmacokinetics and brain target occupancy', Journal of Cerebral Blood Flow and Metabolism, vol. 31, no. 3, pp. 944-952. https://doi.org/10.1038/jcbfm.2010.175
Abanades, Sergio ; van der Aart, Jasper ; Barletta, Julien A. R. ; Marzano, Carmine ; Searle, Graham E. ; Salinas, Cristian A. ; Ahmad, Javaad J. ; Reiley, Richard R. ; Pampols-Maso, Sabina ; Zamuner, Stefano ; Cunningham, Vincent J. ; Rabiner, Eugenii A. ; Laruelle, Marc A. ; Gunn, Roger N. / Prediction of repeat-dose occupancy from single-dose data : characterisation of the relationship between plasma pharmacokinetics and brain target occupancy. In: Journal of Cerebral Blood Flow and Metabolism. 2011 ; Vol. 31, No. 3. pp. 944-952.
@article{ef131b16c3b4437d905137ae104c932a,
title = "Prediction of repeat-dose occupancy from single-dose data: characterisation of the relationship between plasma pharmacokinetics and brain target occupancy",
abstract = "Positron emission tomography (PET) is used in drug development to assist dose selection and to establish the relationship between blood and tissue pharmacokinetics (PKs). We present a new biomathematical approach that allows prediction of repeat-dose (RD) brain target occupancy (TO) using occupancy data obtained after administration of a single dose (SD). A PET study incorporating a sequential adaptive design was conducted in 10 healthy male adults who underwent 4 PET scans with [C-11] DASB ([C-11]N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine): 1 at baseline, 2 after 20mg SD of the 5-hydroxytryptamine transporter (5-HTT) inhibitor duloxetine, and 1 after 4 days daily administration of 20mg duloxetine. An adaptive design was used to select optimal times after SD for measurement of occupancy. Both direct and indirect PK/TO models were fitted to the SD data to characterise the model parameters and then applied to a predicted RD duloxetine plasma time course to predict the 5-HTT occupancy after RD. Repeat-dose prediction from the indirect model (OC50 = 2.62 +/- 0.93 ng/mL) was significantly better (P < 0.05) than that from the direct model (OC50 = 2.29 +/- 1.11 ng/mL). This approach increases the value of SD occupancy studies that are performed as part of first time in human drug development programmes by providing an estimate of the dose required to achieve the desired TO at RD. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 944-952; doi:10.1038/jcbfm.2010.175; published online 13 October 2010",
keywords = "drug occupancy, duloxetine, 5-HTT, mathematical modelling, positron emission tomography (PET), positron-emission-tomography, serotonin transporter, drug development, in-vitro, PET, receptor, perspectives, C-11-DASB, design",
author = "Sergio Abanades and {van der Aart}, Jasper and Barletta, {Julien A. R.} and Carmine Marzano and Searle, {Graham E.} and Salinas, {Cristian A.} and Ahmad, {Javaad J.} and Reiley, {Richard R.} and Sabina Pampols-Maso and Stefano Zamuner and Cunningham, {Vincent J.} and Rabiner, {Eugenii A.} and Laruelle, {Marc A.} and Gunn, {Roger N.}",
year = "2011",
month = "3",
doi = "10.1038/jcbfm.2010.175",
language = "English",
volume = "31",
pages = "944--952",
journal = "Journal of Cerebral Blood Flow and Metabolism",
issn = "0271-678X",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - Prediction of repeat-dose occupancy from single-dose data

T2 - characterisation of the relationship between plasma pharmacokinetics and brain target occupancy

AU - Abanades, Sergio

AU - van der Aart, Jasper

AU - Barletta, Julien A. R.

AU - Marzano, Carmine

AU - Searle, Graham E.

AU - Salinas, Cristian A.

AU - Ahmad, Javaad J.

AU - Reiley, Richard R.

AU - Pampols-Maso, Sabina

AU - Zamuner, Stefano

AU - Cunningham, Vincent J.

AU - Rabiner, Eugenii A.

AU - Laruelle, Marc A.

AU - Gunn, Roger N.

PY - 2011/3

Y1 - 2011/3

N2 - Positron emission tomography (PET) is used in drug development to assist dose selection and to establish the relationship between blood and tissue pharmacokinetics (PKs). We present a new biomathematical approach that allows prediction of repeat-dose (RD) brain target occupancy (TO) using occupancy data obtained after administration of a single dose (SD). A PET study incorporating a sequential adaptive design was conducted in 10 healthy male adults who underwent 4 PET scans with [C-11] DASB ([C-11]N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine): 1 at baseline, 2 after 20mg SD of the 5-hydroxytryptamine transporter (5-HTT) inhibitor duloxetine, and 1 after 4 days daily administration of 20mg duloxetine. An adaptive design was used to select optimal times after SD for measurement of occupancy. Both direct and indirect PK/TO models were fitted to the SD data to characterise the model parameters and then applied to a predicted RD duloxetine plasma time course to predict the 5-HTT occupancy after RD. Repeat-dose prediction from the indirect model (OC50 = 2.62 +/- 0.93 ng/mL) was significantly better (P < 0.05) than that from the direct model (OC50 = 2.29 +/- 1.11 ng/mL). This approach increases the value of SD occupancy studies that are performed as part of first time in human drug development programmes by providing an estimate of the dose required to achieve the desired TO at RD. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 944-952; doi:10.1038/jcbfm.2010.175; published online 13 October 2010

AB - Positron emission tomography (PET) is used in drug development to assist dose selection and to establish the relationship between blood and tissue pharmacokinetics (PKs). We present a new biomathematical approach that allows prediction of repeat-dose (RD) brain target occupancy (TO) using occupancy data obtained after administration of a single dose (SD). A PET study incorporating a sequential adaptive design was conducted in 10 healthy male adults who underwent 4 PET scans with [C-11] DASB ([C-11]N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine): 1 at baseline, 2 after 20mg SD of the 5-hydroxytryptamine transporter (5-HTT) inhibitor duloxetine, and 1 after 4 days daily administration of 20mg duloxetine. An adaptive design was used to select optimal times after SD for measurement of occupancy. Both direct and indirect PK/TO models were fitted to the SD data to characterise the model parameters and then applied to a predicted RD duloxetine plasma time course to predict the 5-HTT occupancy after RD. Repeat-dose prediction from the indirect model (OC50 = 2.62 +/- 0.93 ng/mL) was significantly better (P < 0.05) than that from the direct model (OC50 = 2.29 +/- 1.11 ng/mL). This approach increases the value of SD occupancy studies that are performed as part of first time in human drug development programmes by providing an estimate of the dose required to achieve the desired TO at RD. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 944-952; doi:10.1038/jcbfm.2010.175; published online 13 October 2010

KW - drug occupancy

KW - duloxetine

KW - 5-HTT

KW - mathematical modelling

KW - positron emission tomography (PET)

KW - positron-emission-tomography

KW - serotonin transporter

KW - drug development

KW - in-vitro

KW - PET

KW - receptor

KW - perspectives

KW - C-11-DASB

KW - design

U2 - 10.1038/jcbfm.2010.175

DO - 10.1038/jcbfm.2010.175

M3 - Article

VL - 31

SP - 944

EP - 952

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

SN - 0271-678X

IS - 3

ER -