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    The use of pharmacokinetic and pharmacodynamic end points to determine the dose of AQ4N, a novel hypoxic cell cytotoxin, given with fractionated radiotherapy in a phase I study.

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    Publication date
    2009-11-25T10:26:10Z
    Author
    Steward, W.P.
    Middleton, M.
    Benghiat, A.
    Loadman, Paul M.
    Hayward, C.
    Walter, S.
    Ford, S.
    Halbert, G.
    Patterson, Laurence H.
    Talbot, D.
    Keyword
    AQ4N
    Bioreductive
    Pharmacodynamics
    Pharmacokinetics
    Phase I study
    Peer-Reviewed
    Yes
    
    Metadata
    Show full item record
    Abstract
    Background: AQ4N (1,4-bis[[2-(dimethylamino)ethyl] amino]-5,8-dihydroxyanthracene-9, 10-dione bis-N-oxide dihydrochloride) is a prodrug which is selectively activated within hypoxic tissues to AQ4, a topoisomerase II inhibitor and DNA intercalator. Patients and methods: In the phase I study, 22 patients with oesophageal carcinoma received an i.v. infusion of AQ4N (22.5¿447 mg/m2) followed, 2 weeks later, by further infusion and radiotherapy. Pharmacokinetics and lymphocyte AQ4N and AQ4 levels were measured after the first dose. At 447 mg/m2, biopsies of tumour and normal tissue were taken after AQ4N administration. Results: Drug-related adverse events were blue discolouration of skin and urine, grade 2¿3 lymphopenia, grade 1¿3 fatigue, grade 1¿2 anaemia, leucopenia and nausea. There were no drug-related serious adverse events (SAEs). Three patients had reductions in tumour volume >50%, nine had stable disease. Pharmacokinetics indicated predictable clearance. Plasma area under the curve (AUC) at 447 mg/m2 exceeded AQ4N concentrations in mice at therapeutic doses and tumour biopsies contained concentrations of AQ4 greater than those in normal tissue. Tumour concentrations of AQ4 exceeded in vitro IC50 values for most cell lines investigated. Conclusions: No dose-limiting toxic effects were observed and a maximum tolerated dose was not established. Tumour AQ4 concentrations and plasma AUC at 447 mg/m2 exceeded active levels in preclinical models. This dose was chosen for future studies with radiotherapy.
    URI
    http://hdl.handle.net/10454/3982
    Version
    No full-text available in the repository
    Citation
    Steward, W.P., Middleton, M., Hayward, C., Loadman, P.M. and Patterson, L.H. et al. (2007). The use of pharmacokinetic and pharmacodynamic end points to determine the dose of AQ4N, a novel hypoxic cell cytotoxin, given with fractionated radiotherapy in a phase I study. Annals of Oncology. Vol. 18, No. 6, pp. 1098-1103.
    Link to publisher’s version
    http://dx.doi.org/10.1093/annonc/mdm120
    Type
    Article
    Collections
    Life Sciences Publications

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