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Cancer Chemotherapy and Pharmacology

, Volume 83, Issue 4, pp 787–795 | Cite as

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

  • Alexander MacDonaldEmail author
  • Graeme Scarfe
  • Dominic Magirr
  • Tinnu Sarvotham
  • Julie Charlton
  • Wolfram Brugger
  • Emma Dean
Original Article
  • 47 Downloads

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.

Keywords

Vistusertib AZD2014 ADME Solid malignancies Phase I Metabolism 

Notes

Acknowledgements

The authors would like to thank the Experimental Cancer Medicine Team and Clinical Trials Unit at The Christie NHS Foundation Trust, Stephanie Gaynord (Quintiles, Reading, UK) for study oversight and coordination, Ruth Stow (Covance Metabolism Ltd, Harrogate, UK) for radioactivity measurements, Mark Savage (Unilab Bioanalytical Solutions, York, UK) for metabolite profiling and identification in the biological samples, and Angela Dymond (Covance, Leeds, UK) for the pharmacokinetic analysis.

Funding

This clinical study was sponsored and funded by AstraZeneca.

Compliance with ethical standards

Conflict of interest

All authors are current employees of AstraZeneca.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Alexander MacDonald
    • 1
    Email author
  • Graeme Scarfe
    • 2
  • Dominic Magirr
    • 3
  • Tinnu Sarvotham
    • 4
  • Julie Charlton
    • 4
  • Wolfram Brugger
    • 4
  • Emma Dean
    • 5
    • 6
  1. 1.Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech UnitAstraZenecaRoystonUK
  2. 2.Drug Metabolism and Pharmacokinetics, Oncology IMED, IMED Biotech UnitAstraZenecaCambridgeUK
  3. 3.Early Biometrics, Early Clinical Development, IMED Biotech UnitAstraZenecaCambridgeUK
  4. 4.Translational Medicine Unit, Oncology IMED, IMED Biotech UnitAstraZenecaCambridgeUK
  5. 5.Experimental Cancer Medicine TeamThe University of Manchester and The Christie NHS Foundation TrustManchesterUK
  6. 6.Translational Medicine Unit, Oncology IMED, IMED Biotech UnitAstraZenecaCambridgeUK

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