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

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...

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Bibliographic Details
Published in:	Journal of cerebral blood flow and metabolism Vol. 31; no. 3; pp. 944 - 952
Main Authors:	Abanades, Sergio, van der Aart, Jasper, Barletta, Julien AR, 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
Format:	Journal Article
Language:	English
Published:	London, England SAGE Publications 01-03-2011 Nature Publishing Group Sage Publications Ltd
Subjects:	Adult Benzylamines - metabolism Biological and medical sciences Brain - diagnostic imaging Brain - metabolism Dose-Response Relationship, Drug Drug Administration Schedule Duloxetine Hydrochloride Humans Male Medical sciences Middle Aged Models, Biological Muscle Neurology Original Osmolar Concentration Pharmacology. Drug treatments Positron-Emission Tomography Predictive Value of Tests Radiochemistry - methods Thiophenes - administration & dosage Thiophenes - blood Thiophenes - pharmacokinetics Vascular diseases and vascular malformations of the nervous system 5-HTT duloxetine mathematical modelling drug occupancy positron emission tomography (PET) Nervous system diseases Serotonin Psychotropic Duloxetine Catecholamine Reuptake inhibitor Cerebral disorder Encephalon Central nervous system disease Neurotransmitter Antidepressant agent Norepinephrine Pharmacokinetics Positron emission tomography Cerebrovascular disease Emission tomography
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Summary:	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 [11C]DASB ([11C]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 (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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0271-678X 1559-7016
DOI:	10.1038/jcbfm.2010.175