Pharmacokinetic studies of 9-nitrocamptothecin on intermittent and continuous schedules of administration in patients with solid tumors

Laura L. Jung, Ramesh K. Ramanathan, Merrill J. Egorin, Ruzhi Jin, Chandra P. Belani, Douglas M. Potter, Sandra Strychor, Donald L. Trump, Christine Walko, Marwan Fakih, William C. Zamboni

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Purpose: Oral administration of 9-nitrocamptothecin (9NC), and the formation of its metabolite 9-aminocamptothecin (9AC), may be associated with high interpatient and intrapatient variability. Therefore, we evaluated the plasma pharmacokinetics and urine recovery of 9NC administered on three different schedules as part of phase I and phase II studies. Experimental design: In phase I schedule A, 9NC was administered orally daily for 5 days per week for 2 weeks repeated every 4 weeks. On phase I schedule B, 9NC was administered daily for 14 days repeated every 4 weeks. In Phase II, 9NC was administered daily for 5 days during 8 weeks (one cycle). Serial blood samples were obtained on day 1 and day 10 or 11 for phase I studies, and day 1 and day 50 for the phase II study. Recovery of 9NC and 9AC in urine was evaluated on day 1 and day 10 or 11 in the phase I study. Area under the 9NC and 9AC plasma concentration vs time curves from 0 to 24 h (AUC0-24 h) were calculated using compartmental analysis. Results: The mean ± SD 9NC lactone AUC0-24 h values on day 1 at the maximum tolerated dose of schedules A and B (2.43 and 1.70 mg/m2, respectively) and the phase II dose (1.5 mg/m2) were 78.9 ± 54.4, 155.7 ± 112.8, and 48.3 ± 17.5 ng/ml·h, respectively. The mean ± SD 9AC lactone AUC0-24 h values at these same doses of 9NC were 17.3 ± 17.9, 41.3 ± 16.6, and 31.3 ± 12.8 ng/ml h, respectively. The ratios of 9NC lactone AUC0-24 h on day 10 or 11 to day 1 on phase I A and B were 1.27 ± 0.68 and 1.73 ± 1.56, respectively, and the ratios 9AC lactone AUC0-24 h on day 10 or 11 to day 1 on phase I A and B were 2.23 ± 1.02 and 1.65 ± 0.97, respectively. The recovery of 9NC and 9AC in the urine was < 15%. Conclusions: There was significant interpatient and intrapatient variability in the disposition of 9NC and 9AC. 9NC and 9AC undergo primarily nonrenal elimination.

Original languageEnglish (US)
Pages (from-to)487-496
Number of pages10
JournalCancer chemotherapy and pharmacology
Volume54
Issue number6
DOIs
StatePublished - Dec 1 2004

Keywords

  • 9-Aminocamptothecin
  • 9-Nitrocamptothecin
  • Oral administration
  • Pharmacokinetics

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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    Jung, L. L., Ramanathan, R. K., Egorin, M. J., Jin, R., Belani, C. P., Potter, D. M., Strychor, S., Trump, D. L., Walko, C., Fakih, M., & Zamboni, W. C. (2004). Pharmacokinetic studies of 9-nitrocamptothecin on intermittent and continuous schedules of administration in patients with solid tumors. Cancer chemotherapy and pharmacology, 54(6), 487-496. https://doi.org/10.1007/s00280-004-0835-9