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

doi:10.1038/jcbfm.2010.175

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

NIHR Maudsley Biomedical Research Centre (BRC)

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

59 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 [(11)C]DASB ([(11)C]N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine): 1 at baseline, 2 after 20 mg SD of the 5-hydroxytryptamine transporter (5-HTT) inhibitor duloxetine, and 1 after 4 days daily administration of 20 mg 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 (OC(50)=2.62±0.93 ng/mL) was significantly better (P

Original language	English
Pages (from-to)	944-952
Number of pages	9
Journal	Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
Volume	31
Issue number	3
DOIs	https://doi.org/10.1038/jcbfm.2010.175
Publication status	Published - 2011

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Abanades, S., van der Aart, J., Barletta, J. A. R., Marzano, C., Searle, G. E., Salinas, C. A., Ahmad, J. J., Reiley, R. R., Pampols-Maso, S., Zamuner, S., Cunningham, V. J., Rabiner, E. A., Laruelle, M. A., & Gunn, R. N. (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 : official journal of the International Society of Cerebral Blood Flow and Metabolism, 31(3), 944-952. https://doi.org/10.1038/jcbfm.2010.175

Abanades, Sergio ; van der Aart, Jasper ; Barletta, Julien A R et al. / 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 : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2011 ; Vol. 31, No. 3. pp. 944-952.

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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 [(11)C]DASB ([(11)C]N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine): 1 at baseline, 2 after 20 mg SD of the 5-hydroxytryptamine transporter (5-HTT) inhibitor duloxetine, and 1 after 4 days daily administration of 20 mg 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 (OC(50)=2.62±0.93 ng/mL) was significantly better (P",

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}",

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doi = "10.1038/jcbfm.2010.175",

language = "English",

volume = "31",

pages = "944--952",

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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 : official journal of the International Society of Cerebral Blood Flow and Metabolism, vol. 31, no. 3, pp. 944-952. https://doi.org/10.1038/jcbfm.2010.175

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 et al.
In: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, Vol. 31, No. 3, 2011, p. 944-952.

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

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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

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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 [(11)C]DASB ([(11)C]N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine): 1 at baseline, 2 after 20 mg SD of the 5-hydroxytryptamine transporter (5-HTT) inhibitor duloxetine, and 1 after 4 days daily administration of 20 mg 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 (OC(50)=2.62±0.93 ng/mL) was significantly better (P

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U2 - 10.1038/jcbfm.2010.175

DO - 10.1038/jcbfm.2010.175

M3 - Article

C2 - 20940733

SN - 1559-7016

VL - 31

SP - 944

EP - 952

JO - Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

JF - Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

IS - 3

ER -

Abanades S, van der Aart J, Barletta JAR, Marzano C, Searle GE, Salinas CA et al. 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 : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2011;31(3):944-952. doi: 10.1038/jcbfm.2010.175

Prediction of repeat-dose occupancy from single-dose data: characterisation of the relationship between plasma pharmacokinetics and brain target occupancy

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