@article{discovery1542459,
           month = {April},
         journal = {Toxicology and Applied Pharmacology},
       publisher = {Elsevier},
           title = {Prediction of thyroid C-cell carcinogenicity after chronic administration of GLP1-R agonists in rodents Toxicology and Applied Pharmacology},
            year = {2017},
            note = {{\copyright} 2017 Elsevier Inc. All rights reserved. This manuscript version is made available under a Creative Commons Attribution Non-commercial Non-derivative 4.0 International license (CC BY-NC-ND 4.0). This license allows you to share, copy, distribute and transmit the work for personal and non-commercial use providing author and publisher attribution is clearly stated. Further details about CC BY licenses are available at https://creativecommons.org/licenses/. Access may be initially restricted by the publisher.},
          volume = {320},
           pages = {51--69},
        keywords = {GLP-1r agonists; C-cell carcinogenicity; Pharmacology; PKPD modelling; Prediction},
             url = {http://dx.doi.org/10.1016/j.taap.2017.02.010},
            issn = {1096-0333},
          author = {van den Brink, W and Emerenciana, A and Bellanti, F and Della Pasqua, O and van der Laan, JW},
        abstract = {Increased incidence of C-cell carcinogenicity has been observed for glucagon-like-protein-1 receptor (GLP-1r)
agonists in rodents. It is suggested that the duration of exposure is an indicator of carcinogenic potential in rodents
of the different products on the market. Furthermore, the role of GLP-1-related mechanisms in the induction
of C-cell carcinogenicity has gained increased attention by regulatory agencies. This study proposes an
integrative pharmacokinetic/pharmacodynamic (PKPD) framework to identify explanatory factors and characterize
differences in carcinogenic potential of the GLP-1r agonist products. PK models for four products
(exenatide QW (once weekly), exenatide BID (twice daily), liraglutide and lixisenatide) were developed using
nonlinear mixed effects modelling. Predicted exposure was subsequently linked to GLP-1r stimulation using in
vitro GLP-1r potency data. A logistic regression model was then applied to exenatide QW and liraglutide data
to assess the relationship between GLP-1r stimulation and thyroid C-cell hyperplasia incidence as pre-neoplastic
predictor of a carcinogenic response. The model showed a significant association between predicted GLP-1r stimulation
and C-cell hyperplasia after 2 years of treatment. The predictive performance of the model was evaluated
using lixisenatide, for which hyperplasia data were accurately described during the validation step. The use of a
model-based approach provided insight into the relationship between C-cell hyperplasia and GLP-1r stimulation
for all four products, which is not possible with traditional data analysis methods. It can be concluded that both
pharmacokinetics (exposure) and pharmacodynamics (potency for GLP-1r) factors determine C-cell hyperplasia
incidence in rodents. Our work highlights the pharmacological basis for GLP-1r agonist-induced C-cell carcinogenicity.
The concept is promising for application to other drug classes.}
}