Format

Send to

Choose Destination
See comment in PubMed Commons below
J Cereb Blood Flow Metab. 2013 May;33(5):700-7. doi: 10.1038/jcbfm.2012.208. Epub 2013 Feb 6.

Kinetic analysis of drug-target interactions with PET for characterization of pharmacological hysteresis.

Author information

1
GlaxoSmithKline, Clinical Imaging Centre, Hammersmith Hospital, London, UK.

Abstract

In vivo characterization of the brain pharmacokinetics of novel compounds provides important information for drug development decisions involving dose selection and the determination of administration regimes. In this context, the compound-target affinity is the key parameter to be estimated. However, if compounds exhibit a dynamic lag between plasma and target bound concentrations leading to pharmacological hysteresis, care needs to be taken to ensure the appropriate modeling approach is used so that the system is characterized correctly and that the resultant estimates of affinity are correct. This work focuses on characterizing different pharmacokinetic models that relate the plasma concentration to positron emission tomography outcomes measurements (e.g., volume of distribution and target occupancy) and their performance in estimating the true in vivo affinity. Measured (histamine H3 receptor antagonist--GSK189254) and simulated data sets enabled the investigation of different modeling approaches. An indirect pharmacokinetic-receptor occupancy model was identified as a suitable model for the calculation of affinity when a compound exhibits pharmacological hysteresis.

PMID:
23385202
PMCID:
PMC3652698
DOI:
10.1038/jcbfm.2012.208
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Atypon Icon for PubMed Central
    Loading ...
    Support Center