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    Phase I study of orally administered (14)carbon-isotope labelled-vistusertib (AZD2014), a dual TORC1/2 kinase inhibitor, to assess the absorption, metabolism, excretion, and pharmacokinetics in patients with advanced solid malignancies

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    Authors
    MacDonald, A
    Scarfe, G
    Magirr, D
    Sarvotham, T
    Charlton, J
    Brugger, W
    Dean, Emma J
    Affiliation
    Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Da Vinci Building, Melbourn Science Park, Melbourn, Royston, Herts, SG8 6HB, UK.
    Issue Date
    2019
    
    Metadata
    Show full item record
    Abstract
    PURPOSE: Vistusertib is an orally bioavailable dual target of rapamycin complex (TORC) 1/2 kinase inhibitor currently under clinical investigation in various solid tumour and haematological malignancy settings. The pharmacokinetic, metabolic and excretion profiles of 14Carbon-isotope (14C)-labelled vistusertib were characterised in this open-label phase I patient study. METHODS: Four patients with advanced solid malignancies received a single oral solution dose of 14C-labelled vistusertib. Blood, urine, faeces, and saliva samples were collected at various time points during the 8-day in-patient period of the study. Safety and preliminary efficacy were also assessed. RESULTS: 14C-labelled vistusertib was rapidly absorbed following administration (time to maximum concentration (Tmax) <?1.2 h in all subjects). Overall, >?90% of radioactivity was recovered with the majority recovered as metabolites in faeces (on average 80% vs. 12% recovered in urine). The majority of circulating radioactivity (~?78%) is unchanged vistusertib. Various morpholine-ring oxidation metabolites and an N-methylamide circulate at low concentrations [each <?10% area under the concentration-time curve from zero to infinity (AUC0-?)]. No new or unexpected safety findings were observed; the most common adverse events were nausea and stomatitis. CONCLUSIONS: The pharmacokinetic (PK) profile of vistusertib is similar to previous studies using the same dosing regimen in solid malignancy patients. The majority of vistusertib elimination occurred via hepatic metabolic routes.
    Citation
    MacDonald A, Scarfe G, Magirr D, Sarvotham T, Charlton J, Brugger W, et al. Phase I study of orally administered (14)carbon-isotope labelled-vistusertib (AZD2014), a dual TORC1/2 kinase inhibitor, to assess the absorption, metabolism, excretion, and pharmacokinetics in patients with advanced solid malignancies. Cancer Chemother Pharmacol. 2019 Apr;83(4):787-95.
    Journal
    Cancer Chemotherapy and Pharmacology
    URI
    http://hdl.handle.net/10541/621620
    DOI
    10.1007/s00280-019-03781-x
    PubMed ID
    30758651
    Additional Links
    https://dx.doi.org/10.1007/s00280-019-03781-x
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1007/s00280-019-03781-x
    Scopus Count
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