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Title: Naloxegol, an opioid antagonist with reduced CNS penetration: Mode-of-action and human relevance for rat testicular tumours

Abstract

Naloxegol is an opioid antagonist which has been developed for the treatment of patients with opioid induced constipation. In the nonclinical safety program naloxegol was shown to have a very benign toxicity profile. In the rat, but not the mouse, 2-year carcinogenicity study a change in tumour pattern with an increase in testicular Leydig cell tumours (LCT) was observed after dosing at high (supra-pharmacological) concentrations. To establish the basis of the increase in LCT and to assess its potential relevance to humans, studies to exclude and potentially identify mode-of-action (MoA) were performed. A genotoxic mechanism was ruled out following negative results in the Ames, mouse lymphoma, and micronucleus assays. An effect on androgen metabolism was excluded since the treatment of rats with naloxegol for 14 days did not result in any induction of CYP protein levels. It was demonstrated that administration of centrally restricted opioid antagonists naloxegol or methylnaltrexone at high doses induced an increase in LH release with no clear increase in testosterone, in contrast to the centrally acting opioid antagonist naloxone, which showed marked increases in both LH and testosterone. LCT due to increased LH stimulation is common in rats but not documented in humans. Collectively, the lackmore » of genotoxicity signal, the lack of androgen effect, the increase in LH secretion in rats, which is no considered to be relevant for LCT formation in humans, and high margins to clinical exposures, the observed increase in LCT in the rat is not expected to be clinically relevant. - Highlights: • Naloxegol elicited neuroendocrine responses in form of increased LH release. • In contrast to naloxone, naloxegol did not markedly increase testosterone. • Naloxegol treatment showed increases in rat testicular Leydig cell tumours. • A reduction in pituitary tumours was consistent with opioid antagonism. • Increase in LH mediated rat Leydig cell tumours is not relevant for patients.« less

Authors:
 [1];  [2];  [3];  [2];  [4]
  1. Department of Pathology, Drug Safety & Metabolism, Innovative Medicines and Early Development, AstraZeneca, Gothenburg (Sweden)
  2. Department of Regulatory Safety, Drug Safety & Metabolism, Innovative Medicines and Early Development, AstraZeneca, Cambridge (United Kingdom)
  3. Department of Laboratory Animal Sciences, Drug Safety & Metabolism, Innovative Medicines and Early Development, AstraZeneca, Boston (United States)
  4. (United Kingdom)
Publication Date:
OSTI Identifier:
22722890
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 329; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; LUTEINIZING HORMONE; RATS; TESTES; TESTOSTERONE; TOXICITY

Citation Formats

Andersson, Håkan, Mitchard, Terri, Johnson, Nakpangi, Floettmann, Eike, and AstraZenweca, Department of Non-Clinical Drug Safety, Mundipharma Research Ltd., Cambridge. Naloxegol, an opioid antagonist with reduced CNS penetration: Mode-of-action and human relevance for rat testicular tumours. United States: N. p., 2017. Web. doi:10.1016/J.TAAP.2017.05.032.
Andersson, Håkan, Mitchard, Terri, Johnson, Nakpangi, Floettmann, Eike, & AstraZenweca, Department of Non-Clinical Drug Safety, Mundipharma Research Ltd., Cambridge. Naloxegol, an opioid antagonist with reduced CNS penetration: Mode-of-action and human relevance for rat testicular tumours. United States. doi:10.1016/J.TAAP.2017.05.032.
Andersson, Håkan, Mitchard, Terri, Johnson, Nakpangi, Floettmann, Eike, and AstraZenweca, Department of Non-Clinical Drug Safety, Mundipharma Research Ltd., Cambridge. Tue . "Naloxegol, an opioid antagonist with reduced CNS penetration: Mode-of-action and human relevance for rat testicular tumours". United States. doi:10.1016/J.TAAP.2017.05.032.
@article{osti_22722890,
title = {Naloxegol, an opioid antagonist with reduced CNS penetration: Mode-of-action and human relevance for rat testicular tumours},
author = {Andersson, Håkan and Mitchard, Terri and Johnson, Nakpangi and Floettmann, Eike and AstraZenweca, Department of Non-Clinical Drug Safety, Mundipharma Research Ltd., Cambridge},
abstractNote = {Naloxegol is an opioid antagonist which has been developed for the treatment of patients with opioid induced constipation. In the nonclinical safety program naloxegol was shown to have a very benign toxicity profile. In the rat, but not the mouse, 2-year carcinogenicity study a change in tumour pattern with an increase in testicular Leydig cell tumours (LCT) was observed after dosing at high (supra-pharmacological) concentrations. To establish the basis of the increase in LCT and to assess its potential relevance to humans, studies to exclude and potentially identify mode-of-action (MoA) were performed. A genotoxic mechanism was ruled out following negative results in the Ames, mouse lymphoma, and micronucleus assays. An effect on androgen metabolism was excluded since the treatment of rats with naloxegol for 14 days did not result in any induction of CYP protein levels. It was demonstrated that administration of centrally restricted opioid antagonists naloxegol or methylnaltrexone at high doses induced an increase in LH release with no clear increase in testosterone, in contrast to the centrally acting opioid antagonist naloxone, which showed marked increases in both LH and testosterone. LCT due to increased LH stimulation is common in rats but not documented in humans. Collectively, the lack of genotoxicity signal, the lack of androgen effect, the increase in LH secretion in rats, which is no considered to be relevant for LCT formation in humans, and high margins to clinical exposures, the observed increase in LCT in the rat is not expected to be clinically relevant. - Highlights: • Naloxegol elicited neuroendocrine responses in form of increased LH release. • In contrast to naloxone, naloxegol did not markedly increase testosterone. • Naloxegol treatment showed increases in rat testicular Leydig cell tumours. • A reduction in pituitary tumours was consistent with opioid antagonism. • Increase in LH mediated rat Leydig cell tumours is not relevant for patients.},
doi = {10.1016/J.TAAP.2017.05.032},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = ,
volume = 329,
place = {United States},
year = {2017},
month = {8}
}