Safety, tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent kinase inhibitor AZD5438 when administered at intermittent and continuous dosing schedules in patients with advanced solid tumours Journal Article

   

Authors:	Boss, D. S.; Schwartz, G. K.; Middleton, M. R.; Amakye, D. D.; Swaisland, H.; Midgley, R. S.; Ranson, M.; Danson, S.; Calvert, H.; Plummer, R.; Morris, C.; Carvajal, R. D.; Chirieac, L. R.; Schellens, J. H. M.; Shapiro, G. I.
Article Title:	Safety, tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent kinase inhibitor AZD5438 when administered at intermittent and continuous dosing schedules in patients with advanced solid tumours
Abstract:	Background: AZD5438 is an orally bioavailable inhibitor of cyclin E-cdk2, cyclin A-cdk2 and cyclin B-cdk1 complexes. Three phase I studies assessed the clinical safety, tolerability, pharmacokinetics and pharmacodynamics of AZD5438 when administered in different dosing schedules. Patients and methods: AZD5438 was administered four times daily, once every 7 days (study 1), for 14 consecutive days followed by 7 days of rest (study 2), or continuously (study 3), to patients with advanced solid tumours. Dose escalation proceeded until the emergence of dose-limiting toxic effects. Results: Sixty-four patients were included across the three studies (19, 17 and 28, respectively). Nausea and vomiting were the most common adverse events. When dosed continuously, 40 mg four times daily was considered intolerable, and due to safety issues, all studies were terminated prematurely. Consequently, no intolerable dose was identified during the weekly schedule. Pharmacokinetics demonstrated dose-proportional exposure, high interpatient variability and accumulation after multiple doses. Skin biopsies indicated reduced retinoblastoma protein phosphorylation at cdk2 phospho-sites; other pharmacodynamic assessments did not reveal consistent trends. Conclusions: AZD5438 was generally well tolerated in a weekly dosing schedule, but not in continuous schedules. The clinical development programme for AZD5438 was discontinued owing to tolerability and exposure data from these studies.
Keywords:	carboplatin; apoptosis; pharmacodynamics; phosphorylation; flavopiridol; retinoblastoma protein; phase-i; cell-cycle; inactivation; azd5438; cyclin-dependent kinase inhibitor; hair follicle analysis; healthy male-volunteers
Journal Title:	Annals of Oncology
Volume:	21
Issue:	4
ISSN:	0923-7534
Publisher:	Oxford University Press
Date Published:	2010-04-01
Start Page:	884
End Page:	894
Language:	English
ACCESSION:	ISI:000276045600033
DOI:	10.1093/annonc/mdp377
PROVIDER:	wos
PMCID:	PMC2844945
PUBMED:	19825886
Notes:	--- - Editorial Material - "Source: Wos"

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