Alternative administration of camptothecin analogues

C. F. Verschraegen, Kurt Jaeckle, B. Giovanella, V. Knight, B. E. Gilbert

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The binding of camptothecin (CPT) to the DNA-topoisomerase complex is reversible, but it needs to be maintained for maximal inhibitory activity. It is also dependent on the chemical structure of CPT. The lactone form is thought to be necessary for the activity. In human serum, the equilibrium between lactone and carboxylate is in favor of the latter. For these reasons, alternative administration of CPT analogues is being evaluated. The ideal compound would remain in lactone form and would expose the host for long periods of time to its effects. Oral administration of irinotecan (CPT-11) and topotecan (TPT) is discussed by other investigators. We studied oral rubitecan and reported a low lactone to total drug area under the plasma concentration-time curve (AUCp) ratio (14.7%), with low plasma concentration over time despite repeated administrations and the presence of an enterohepatic cycle. Aerosolization of a liposomal formulation of rubitecan is currently under study. Six patients have been treated once a day for 5 days every 3 weeks. The dose was 6.7 μg/kg/day. Plasma levels are dose for dose higher than those after oral administration, but the ratio of lactone versus total drug is low. No toxicity was observed. The study will continue with increasing doses and lengths of administration. Intrathecal administration of topotecan has been studied in a phase I trial in children. Doses of 0.4 mg are tolerated without toxicity, and clinical responses have been seen in patients with refractory meningial carcinomatosis. Phase II studies are planned. Intraperitoneal (ip) administration of topotecan has been studied in a phase I trial as a 24-hour infusion in 5% dextrose at pH 3.5 every 21 days. Dose-limiting toxicity is 4 mg/m2. Toxic effects are neutropenia, anemia, emesis, fever, and pain. Five of 10 patients with ascites had symptomatic relief. Pharmacokinetic analysis demonstrates a second-order kinetics with elimination half-lives of 0.49 and 2.7 hours. The peritoneal to plasma AUC ratio was 31.2. Intramuscular, transdermal, and subcutaneous administrations have been extensively studied in the mouse.

Original languageEnglish (US)
Pages (from-to)237-246
Number of pages10
JournalAnnals of the New York Academy of Sciences
Volume922
StatePublished - Jan 1 2000

Fingerprint

Camptothecin
Lactones
irinotecan
Topotecan
Oral Administration
Toxicity
Plasmas
Cutaneous Administration
Type I DNA Topoisomerase
Poisons
Neutropenia
Ascites
Pharmaceutical Preparations
Area Under Curve
Vomiting
Anemia
Fever
Pharmacokinetics
Research Personnel
Dose

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

Cite this

Verschraegen, C. F., Jaeckle, K., Giovanella, B., Knight, V., & Gilbert, B. E. (2000). Alternative administration of camptothecin analogues. Annals of the New York Academy of Sciences, 922, 237-246.
Verschraegen, C. F. ; Jaeckle, Kurt ; Giovanella, B. ; Knight, V. ; Gilbert, B. E. / Alternative administration of camptothecin analogues. In: Annals of the New York Academy of Sciences. 2000 ; Vol. 922. pp. 237-246.
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Verschraegen, CF, Jaeckle, K, Giovanella, B, Knight, V & Gilbert, BE 2000, 'Alternative administration of camptothecin analogues', Annals of the New York Academy of Sciences, vol. 922, pp. 237-246.

Alternative administration of camptothecin analogues. / Verschraegen, C. F.; Jaeckle, Kurt; Giovanella, B.; Knight, V.; Gilbert, B. E.

In: Annals of the New York Academy of Sciences, Vol. 922, 01.01.2000, p. 237-246.

Research output: Contribution to journalArticle

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Verschraegen CF, Jaeckle K, Giovanella B, Knight V, Gilbert BE. Alternative administration of camptothecin analogues. Annals of the New York Academy of Sciences. 2000 Jan 1;922:237-246.