Predictions of In Vivo Prolactin Levels from In Vitro Ki Values of D2 Receptor Antagonists Using an Agonist–Antagonist Interaction Model
Journal Title: The AAPS Journal - Year 2013, Vol 15, Issue 2
Abstract
Prolactin elevation is a side effect of all currently available D2 receptor antagonists used in the treatment of schizophrenia. Prolactin elevation is the result of a direct antagonistic D2 effect blocking the tonic inhibition of prolactin release by dopamine. The aims of this work were to assess the correlation between in vitro estimates of D2 receptor affinity and pharmacokinetic–pharmacodynamic model-based estimates obtained from analysis of clinical data using an agonist–antagonist interaction (AAI) model and to assess the value of such a correlation in early prediction of full prolactin time profiles. A population model describing longitudinal prolactin data was fitted to clinical data from 16 clinical phases 1 and 3 trials including five different compounds. Pharmacokinetic data were modeled for each compound and the prolactin model was both fitted in per-compound fits as well as simultaneously to all prolactin data. Estimates of prolactin elevating potency were compared to corresponding in vitro values and their predictability was evaluated through model-based simulations. The model successfully described the prolactin time course for all compounds. Estimates derived from experimental preclinical data and the model fit of the clinical data were strongly correlated (p < 0.001), and simulations adequately predicted the prolactin elevation in five out of six compounds. The AAI model has the potential to be used in drug development to predict prolactin response for a given exposure of D2 antagonists using routinely produced preclinical data.
Authors and Affiliations
Klas J. Petersson, An M. Vermeulen, Lena E. Friberg
Keywords
Related Articles
- EP ID EP681105
- DOI 10.1208/s12248-012-9450-6
- Views 49
- Downloads 0
Development and Fit-for-Purpose Validation of a Soluble Human Programmed Death-1 Protein Assay
The online version of this article (doi:10.1208/s12248-015-9762-4) contains supplementary material, which is available to authorized users.
Cellular Uptake Mechanism of Paclitaxel Nanocrystals Determined by Confocal Imaging and Kinetic Measurement
The online version of this article (doi:10.1208/s12248-015-9774-0) contains supplementary material, which is available to authorized users.
Amino-Terminated Generation 2 Poly(amidoamine) Dendrimer as a Potential Broad-Spectrum, Nonresistance-Inducing Antibacterial Agent
The online version of this article (doi:10.1208/s12248-012-9416-8) contains supplementary material, which is available to authorized users.
Immunotoxins for targeted cancer therapy
Immunotoxins are proteins that contain a toxin along with an antibody or growth factor that binds specifically to target cells. Nearly all protein toxins work by enzymatically inhibiting protein synthesis. For the immuno...
Development of an In Vivo Ovine Dry Powder Inhalation Model for the Evaluation of Conventional and Controlled Release Microparticles
Microparticles of DSCG alone or with 90% w/w PVA where prepared and characterised as described previously (5,6). Briefly, DSCG was spray dried under optimised conditions to produce a yield of microparticles with desired...