The camptothecins : alternative assessments of their pharmacology, toxicity and clinical efficacy

The work presented in this thesis has concentrated on the camptothecins, specifically Irinotecan (Ir) and 9-aminocamptothecin (9AC). Based on the significant issues regarding their variable pharmacokinetics (PK) and pharmacodynamics (PD), four hypotheses were developed and tested through prospective clinical trials and PK-PD studies. The overall theme of this body of work was to explore alternative assessments of the pharmacology, toxicity and clinical efficacy of these agents to enable the potential individualisation of their use in patients.

These abbreviated hypotheses are listed below (in italics) together with an outline of their corresponding salient results:

(i) Functional hepatic imaging and genetic polymorphisms of drug excretory/metabolic pathways may provide better prediction of Irinotecan clearance and toxicity than standard dosing: In a prospective trial, pre-therapy 99mTechnetium (Tc)-MIBI and 99mTc-IDA analogue hepatic nuclear imaging (HNI) parameters were found to correlate significantly with SN38 exposure (AUC), the active moiety of Ir. Positive trends were also observed between increasing severity of Ir toxicities and HNI parameters. These results represent the first report evaluating non-invasive functional hepatic imaging as a potential method of predicting Ir metabolism/excretion and toxicity.

(ii) PD models for 9AC-induced neutropenia that incorporate drug effect upon the bone marrow may better predict this toxicity than standard exposure models based upon its AUC or Css: A retrospective PD analysis of a phase I trial of 9AC given as 4 infusions (days 1, 8, 15, 22, q 5 weeks) demonstrated that non-linear exposure models using day 1 9AC-Lactone AUC and Css or a cumulative 9AC-Lactone AUC function correlated with the day 15 neutropenia. An effect compartment approach was also used to model the inhibitory effect of 9AC-Lactone upon bone marrow neutrophil production. This model defined the variation of the neutrophil counts over a 5 week treatment course, albeit with several caveats. This latter approach however requires further refinement.

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