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    A phase I and pharmacokinetic study of amphethinile.

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    Authors
    Smith, David B
    Ewen, C
    Mackintosh, J
    Fox, Brian W
    Thatcher, Nick
    Scarffe, J Howard
    Vezin, R
    Crowther, Derek
    Affiliation
    CRC Department of Medical Oncology, Christie Hospital, Manchester, UK.
    Issue Date
    1988-06
    
    Metadata
    Show full item record
    Abstract
    Amphethinile is a new spindle poison with a novel structure that has shown activity in the L1210, ADJ/PC6 and Walker carcinoma rodent tumours. In addition the agent appeared to have an improved therapeutic ratio compared to existing spindle poisons and is well absorbed when administered orally. The starting dose for the phase I study was 40 mg m-2 (1/10th mouse LD10) and further patients were studied at 200, 400, 800 and 1200 mg m-2, dose escalation being based on pharmacological monitoring. Significant toxic effects were seen only at 800 and 1200 mg m-2. At these doses patients experienced nausea and vomiting, light headedness during the infusion and varying degrees of lethargy following therapy. Two of six patients at 800 mg m-2 developed severe pain in the tumour bearing area 1-2 h after treatment and one experienced colicky abdominal pain. At 1200 mg m-2 two patients died within 48 h of treatment from what appeared to be vascular causes. Following these episodes the trial was discontinued. Neutropenia and alopecia occurred in two patients, one at 800 and one at 1200 mg m-2. These patients achieved the highest drug exposure in terms of area under the concentration x time curve. It was not possible to achieve an AUC consistently high enough to produce cytotoxic effects due to the occurrence of dose limiting toxicities thus amphethinile cannot at present be recommended for phase II testing by the i.v. route. The dose escalation scheme based on pharmacological monitoring resulted in a considerable saving in the duration of the trial. Further evaluation of this methodology is recommended.
    Citation
    A phase I and pharmacokinetic study of amphethinile. 1988, 57 (6):623-7 Br. J. Cancer
    Journal
    British Journal of Cancer
    URI
    http://hdl.handle.net/10541/108133
    PubMed ID
    3408647
    Type
    Article
    Language
    en
    ISSN
    0007-0920
    Collections
    All Christie Publications
    All Paterson Institute for Cancer Research

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