title: The value of integrating pre-clinical data to predict nausea and vomiting risk in humans as illustrated by AZD3514, a novel androgen receptor modulator.
abstract: Nausea and vomiting are components of a complex mechanism that signals food avoidance and protection of the body against the absorption of ingested toxins. This response can also be triggered by pharmaceuticals. Predicting clinical nausea and vomiting liability for pharmaceutical agents based on pre-clinical data can be problematic as no single animal model is a universal predictor. Moreover, efforts to improve models are hampered by the lack of translational animal and human data in the public domain. AZD3514 is a novel, orally-administered compound that inhibits androgen receptor signaling and down-regulates androgen receptor expression. Here we have explored the utility of integrating data from several pre-clinical models to predict nausea and vomiting in the clinic. Single and repeat doses of AZD3514 resulted in emesis, salivation and gastrointestinal disturbances in the dog, and inhibited gastric emptying in rats after a single dose. AZD3514, at clinically relevant exposures, induced dose-responsive "pica" behaviour in rats after single and multiple daily doses, and induced retching and vomiting behaviour in ferrets after a single dose. We compare these data with the clinical manifestation of nausea and vomiting encountered in patients with castration-resistant prostate cancer receiving AZD3514. Our data reveal a striking relationship between the pre-clinical observations described and the experience of nausea and vomiting in the clinic. In conclusion, the emetic nature of AZD3514 was predicted across a range of pre-clinical models, and the approach presented provides a valuable framework for predicition of clinical nausea and vomiting.
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, United Kingdom. Electronic address: claire.grant@astrazeneca.com.
authors.forename: Claire
authors.initials: C
authors.lastname: Grant
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Da Vinci Building, Melbourn Science Park, Cambridge Road, Melbourn, Royston SG8 6HB, United Kingdom.
authors.forename: Lorna
authors.initials: L
authors.lastname: Ewart
authors.affiliation: Respiratory, Inflammation and Autoimmunity iMED, AstraZeneca, Pepparedsleden 1, 431 83 Mölndal, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Muthas
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, United Kingdom.
authors.forename: Damian
authors.initials: D
authors.lastname: Deavall
authors.affiliation: Oncology Translational Medicine Unit, Early Clinical Development, AstraZeneca, Da Vinci Building, Melbourn Science Park, Melbourn, Royston SG8 6HB, United Kingdom.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Smith
authors.affiliation: Translational Medicine Unit, Early Clinical Development, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, United Kingdom.
authors.forename: Glen
authors.initials: G
authors.lastname: Clack
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Darwin Building, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, United Kingdom.
authors.forename: Pete
authors.initials: P
authors.lastname: Newham
mesh_terms: D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005289:Ferrets; D006801:Humans; D008297:Male; D023421:Models, Animal; D009325:Nausea / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis; D011237:Predictive Value of Tests; D011724:Pyridazines / Q000009:adverse effects*; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000502:physiology*; D014839:Vomiting / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis
chemical_list: C583656:AZD3514; D011724:Pyridazines; D011944:Receptors, Androgen
keywords: Gastrointestinal adverse effects; Nausea; Pre-clinical animal models; Translation; Vomiting