van den Brink, W;
Emerenciana, A;
Bellanti, F;
Della Pasqua, O;
van der Laan, JW;
(2017)
Prediction of thyroid C-cell carcinogenicity after chronic administration of GLP1-R agonists in rodents Toxicology and Applied Pharmacology.
Toxicology and Applied Pharmacology
, 320
pp. 51-69.
10.1016/j.taap.2017.02.010.
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Della Pasqua_20170207_GLP-1_carc_Manuscript_final_revised.pdf - Accepted Version Available under License : See the attached licence file. Download (1MB) | Preview |
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Della Pasqua_20170207_GLP-1_carc_Manuscript SUPPLEMENTARY MATERIAL.pdf - Accepted Version Available under License : See the attached licence file. Download (450kB) | Preview |
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.
| Type: | Article |
|---|---|
| Title: | Prediction of thyroid C-cell carcinogenicity after chronic administration of GLP1-R agonists in rodents Toxicology and Applied Pharmacology |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.taap.2017.02.010 |
| Publisher version: | http://dx.doi.org/10.1016/j.taap.2017.02.010 |
| Language: | English |
| Additional information: | © 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. |
| Keywords: | GLP-1r agonists; C-cell carcinogenicity; Pharmacology; PKPD modelling; Prediction |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1542459 |
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