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

2017-02-08T04:47:22Z (GMT) by Michael, Michael
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. (iii) Activated Charcoal (AC), through adsorbing intestinal lumen SN38, may reduce the dose-limiting diarrhea induced by Ir and enhance its dose intensity. The consumption of the anti-diarrheal agent loperamide may provide a surrogate marker of response for AC: In a prospective trial, 28 patients received prophylactic AC in course 1 of Ir and not in course 2. The grade 3 and 4 diarrhea rate in course 1 was 7.1% versus 25% in course 2 and the rate of grade 0 diarrhea was 46.4% versus 20.8%, respectively. This corresponded to a reduced loperamide utilisation in course 1. The median percentage of the planned Ir dose actually delivered in course 1 versus course 2 was 98% versus 70%, respectively. This represents the first study evaluating the use of prophylactic AC in the reduction of Ir-induced diarrhea and demonstrated promising efficacy. (iv) Clinical benefit response, based upon performance status, pain intensity and analgesic use, may provide a prospective measure of irinotecan’s palliative effects in patients with previously treated advanced colorectal cancer (CRC): A prospective phase II trial of Ir in CRC utilised clincial benefit response as the primary efficacy endpoint. A total of 65 patients were entered onto the study and a clinical benefit response was achieved in 27 patients (42%), which was higher than the radiological response rate (11%). This represents the first such study to evaluate palliative or clincial benefit response as a primary endpoint of Ir therapy in CRC.