The camptothecins are DNA topoisomerase I-interactive anticancer agents and have a wide range of antitumor activity. Currently approved camptothecin analogues (i.e., topotecan and irinotecan) are only available for IV administration. 9-Nitrocamptothecin (9NC) is administered orally and is partially metabolized to an active metabolite, 9-aminocamptothecin (9AC). As with other camptothecin analogues, 9NC and 9AC undergo a reversible, pH-dependent reaction between the active-lactone and inactive-hydroxy acid forms. In vitro and in vivo preclinical studies suggest that protracted administration of low doses of camptothecin analogues produces better antitumor activity than the less frequent administration of higher doses. Oral administration of 9NC could mimic the protracted schedule and maximize patient convenience. However, the optimal oral dose and schedule of 9NC and other camptothecin analogues are currently unclear. In addition, oral administration of camptothecin analogues has been characterized by extensive inter- and intra-patient variability in bioavailability. The primary goal of this dissertation research was to evaluate the pharmacokinetics and pharmacogenetics of 9NC and its 9AC metabolite in preclinical models and in patients as part of phase I and II trails.
Daily administration of 9NC orally for 5 days per week for two consecutive weeks repeated every four weeks is tolerable and may be an active regimen in patients with gastric or pancreatic cancers. The responses seen in xenografts models evaluating the same regimen of 9NC as evaluated in the phase I study occurred at systemic exposures that are tolerable in patients. There was significant inter- and intra-patient variability in the pharmacokinetics of 9NC and 9AC when 9NC was administered under fasting conditions. Most of the drug remained in the 9NC form with an overall ratio of 9NC to 9AC of 4:1. Co-administration of 9NC with food reduces the oral absorption of 9NC; however there was no difference in the exposure of 9AC. The functional consequences of known single nucleotide polymorphisms in genes of known ATP-binding cassette (ABC) transporters were evaluated as potential sources of the pharmacokinetic variability of 9NC and 9AC. Our findings suggest that the inter-individual variability in the disposition of 9AC, but not 9NC, may be influenced, in part, by ABCG2 genotype. The factors associated with the high inter- and intra-patient variability remain unclear.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-08222005-141856 |
| Date | 20 December 2005 |
| Creators | Zamboni, William Christopher |
| Contributors | John W. Wilson, Raman Venkataramanan, Howard McLeod, Reginald Frye, Merrill J. Egorin |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-08222005-141856/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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