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. 1999 Jul;80(9):1380–1386. doi: 10.1038/sj.bjc.6690532

Oral topotecan: bioavailability and effect of food co-administration

V M M Herben 1,2, H Rosing 1, W W ten Bokkel Huinink 2, D M van Zomeren 1, D Batchelor 2, E Doyle 3, F D Beusenberg 4, J H Beijnen 1,2, J H M Schellens 2
PMCID: PMC2363072  PMID: 10424739

Abstract

The aims of the study were twofold: (1) to evaluate the effect of food on the relative oral bioavailability of topotecan gelatin capsules in patients with solid tumours, and (2) to determine the absolute bioavailability of oral topotecan with reference to the intravenous (i.v.) formulation. The study had a randomized two-period cross-over design. On day 1 of the first treatment course patients were administered 2.3 mg m−2 day−1 of oral topotecan with or without a high-fat breakfast. They crossed over to receive the alternate regimen on day 2. In the second course (3 weeks later) fasted patients received topotecan orally (2.3 mg m−2 day−1) or i.v. (1.5 mg m−3 day). They crossed over to receive the alternate regimen on day 2. On days 3–5 of both treatment courses patients received oral topotecan. Plasma pharmacokinetics were performed on days 1 and 2 of the first and second course using a high-performance liquid chromatographic assay. Eighteen patients were enrolled in the study. The ratio of the area under the curve to infinity during fasted and high-fat treatment was 0.93 ± 0.23 (90% confidence interval (CI) 0.83–1.03). Maximal plasma concentrations of topotecan were similar after ingestion of the capsules with (10.6 ± 4.4 ng ml−1) or without food (9.2 ± 4.1 ng ml−1) (P = 0.130). The time needed to reach maximal plasma levels was significantly prolonged after food intake (median 3.1 h, range 2.8–6.1) compared to fasted conditions (2.0 h, range 1.1–8.1) (P = 0.013). The absolute bioavailability of topotecan averaged 42 ± 13% (90% CI 37– 47%). The apparent terminal half-life was significantly longer after administration of oral topotecan (3.9 ± 1.0 h) than after i.v. administration (2.7 ± 0.4 h) (P < 0.001). Topotecan demonstrates suitable bioavailability for oral treatment. Co-administration of the topotecan gelatin capsules with a high-fat breakfast leads to a small decrease in absorption rate but does not affect the extent of absorption. © 1999 Cancer Research Campaign

Keywords: topotecan, oral, bioavailability, food

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Selected References

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  1. Ajani J. A., Welch S. R., Raber M. N., Fields W. S., Krakoff I. H. Comprehensive criteria for assessing therapy-induced toxicity. Cancer Invest. 1990;8(2):147–159. doi: 10.3109/07357909009017560. [DOI] [PubMed] [Google Scholar]
  2. Burris H. A., 3rd, Hanauske A. R., Johnson R. K., Marshall M. H., Kuhn J. G., Hilsenbeck S. G., Von Hoff D. D. Activity of topotecan, a new topoisomerase I inhibitor, against human tumor colony-forming units in vitro. J Natl Cancer Inst. 1992 Dec 2;84(23):1816–1820. doi: 10.1093/jnci/84.23.1816. [DOI] [PubMed] [Google Scholar]
  3. Creemers G. J., Gerrits C. J., Eckardt J. R., Schellens J. H., Burris H. A., Planting A. S., Rodriguez G. I., Loos W. J., Hudson I., Broom C. Phase I and pharmacologic study of oral topotecan administered twice daily for 21 days to adult patients with solid tumors. J Clin Oncol. 1997 Mar;15(3):1087–1093. doi: 10.1200/JCO.1997.15.3.1087. [DOI] [PubMed] [Google Scholar]
  4. Herben V. M., ten Bokkel Huinink W. W., Dubbelman A. C., Mandjes I. A., Groot Y., van Gortel-van Zomeren D. M., Beijnen J. H. Phase I and pharmacological study of sequential intravenous topotecan and oral etoposide. Br J Cancer. 1997;76(11):1500–1508. doi: 10.1038/bjc.1997.585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Hertzberg R. P., Caranfa M. J., Holden K. G., Jakas D. R., Gallagher G., Mattern M. R., Mong S. M., Bartus J. O., Johnson R. K., Kingsbury W. D. Modification of the hydroxy lactone ring of camptothecin: inhibition of mammalian topoisomerase I and biological activity. J Med Chem. 1989 Mar;32(3):715–720. doi: 10.1021/jm00123a038. [DOI] [PubMed] [Google Scholar]
  6. Houghton P. J., Cheshire P. J., Hallman J. D., 2nd, Lutz L., Friedman H. S., Danks M. K., Houghton J. A. Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol. 1995;36(5):393–403. doi: 10.1007/BF00686188. [DOI] [PubMed] [Google Scholar]
  7. Hsiang Y. H., Liu L. F. Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res. 1988 Apr 1;48(7):1722–1726. [PubMed] [Google Scholar]
  8. Hsiang Y. H., Liu L. F., Wall M. E., Wani M. C., Nicholas A. W., Manikumar G., Kirschenbaum S., Silber R., Potmesil M. DNA topoisomerase I-mediated DNA cleavage and cytotoxicity of camptothecin analogues. Cancer Res. 1989 Aug 15;49(16):4385–4389. [PubMed] [Google Scholar]
  9. Marzo A., Balant L. P. Bioequivalence. An updated reappraisal addressed to applications of interchangeable multi-source pharmaceutical products. Arzneimittelforschung. 1995 Feb;45(2):109–115. [PubMed] [Google Scholar]
  10. Pabst G., Jaeger H. Review of methods and criteria for the evaluation of bioequivalence studies. Eur J Clin Pharmacol. 1990;38(1):5–10. doi: 10.1007/BF00314794. [DOI] [PubMed] [Google Scholar]
  11. Rosing H., Doyle E., Davies B. E., Beijnen J. H. High-performance liquid chromatographic determination of the novel antitumour drug topotecan and topotecan as the total of the lactone plus carboxylate forms, in human plasma. J Chromatogr B Biomed Appl. 1995 Jun 9;668(1):107–115. doi: 10.1016/0378-4347(95)00054-m. [DOI] [PubMed] [Google Scholar]
  12. Rosing H., Herben V. M., van Gortel-van Zomeren D. M., Hop E., Kettenes-van den Bosch J. J., ten Bokkel Huinink W. W., Beijnen J. H. Isolation and structural confirmation of N-desmethyl topotecan, a metabolite of topotecan. Cancer Chemother Pharmacol. 1997;39(6):498–504. doi: 10.1007/s002800050605. [DOI] [PubMed] [Google Scholar]
  13. Schellens J. H., Creemers G. J., Beijnen J. H., Rosing H., de Boer-Dennert M., McDonald M., Davies B., Verweij J. Bioavailability and pharmacokinetics of oral topotecan: a new topoisomerase I inhibitor. Br J Cancer. 1996 May;73(10):1268–1271. doi: 10.1038/bjc.1996.243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Underberg W. J., Goossen R. M., Smith B. R., Beijnen J. H. Equilibrium kinetics of the new experimental anti-tumour compound SK&F 104864-A in aqueous solution. J Pharm Biomed Anal. 1990;8(8-12):681–683. doi: 10.1016/0731-7085(90)80102-u. [DOI] [PubMed] [Google Scholar]

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