Studies on the dose banding of Paclitaxel

Xu, Jing (2009) Studies on the dose banding of Paclitaxel. (PhD thesis), Kingston University.

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Abstract

Paclitaxel is an important chemotherapeutic agent and is used in the treatment of many solid tumours including ovarian cancer, NSCLC, and breast cancer, with further applications under evaluation in clinical trials. In current practice, the dosage of paclitaxel is calculated according to body-surface area (BSA). However the scientific validity of individualised BSA-based dosing has been doubted for many years. In the case of paclitaxel, alternative dosing strategies such as flat-fixed dosing and dose-banding have been considered. However, prior to the studies reported in this thesis, no evidence was available to support the pharmaceutical and clinical implications of such strategies. This thesis includes a literature review, outlining the role of chemotherapy in the treatment of cancer and a detailed appraisal of paclitaxel from both clinical and pharmaceutical prospective. Robust stability data on ready-to-use preparations are required to support the inclusion of medicines in dose-banding (D-B) schemes. Studies on the physical and chemical stability of paclitaxel infusions are described of drug concentrations relevant to D-B. A clinical and pharmacokinetic study is described which was designed to assess the clinical effect of paclitaxel D-B, and to compare D-B with individualised BSA-based dosing and flat-fixed dosing schemes. This study used area under the plasma concentration-time curve (AUC) to assess effect of dose schedule on exposure of tissues to the drug. This was considered an appropriate surrogate for therapeutic effect and toxicity. Validated methods for the processing and analysis of plasma samples were a pre-requisite for this study and the development and validation of these methods are described in Chapter 3 of this thesis. External factors precluded implementation of the clinical-pharmacokinetic study and therefore a novel ‘ex vivo’ pharmacokinetic model was designed to simulate the clinical PK study. This laboratory simulation was developed and scaled-down from ‘in vivo’ data. This ‘ex vivo’ study suggested there was no significant difference between the D-B dosing and the individualised BSA-based dosing as well as between the flat-fixed dosing and the individualised dosing of paclitaxel on the basis of likely exposure of the tissues to the drug.

Item Type: Thesis (PhD)
Physical Location: This item is held in stock at Kingston University Library.
Research Area: Pharmacy
Faculty, School or Research Centre: Faculty of Science (until 2011)
Depositing User: Automatic Import Agent
Date Deposited: 09 Sep 2011 21:38
Last Modified: 02 Oct 2014 09:27
URI: http://eprints.kingston.ac.uk/id/eprint/20411

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