Bioavailability and pharmacokinetics of oral topotecan: a new topoisomerase I inhibitor
Open Access
- 1 May 1996
- journal article
- clinical trial
- Published by Springer Science and Business Media LLC in British Journal of Cancer
- Vol. 73 (10), 1268-1271
- https://doi.org/10.1038/bjc.1996.243
Abstract
The results of preclinical and clinical studies indicate enhanced antineoplastic activity of topotecan (SKF 104864-A) when administered as a chronic treatment. We determined the apparent bioavailability and pharmacokinetics of topotecan administered orally to 12 patients with solid tumours in a two-part crossover study. The oral dose of 1.5 mg m-2 was administered as a drinking solution of 200 ml on day 1. The i.v. dose of 1.5 mg m-2 was administered as a 30 min continuous infusion on day 2. The bioavailability was calculated as the ratio of the oral to i.v. area under the curve (AUC) calculated up to the last measured time point. The oral drinking solution was well tolerated. The bioavailability revealed moderate inter-patient variation and was 30% +/- 7.7% (range 21-45%). The time to maximum plasma concentration after oral administration (Tmax) was 0.78 h (median; range 0.33-2.5). Total i.v. plasma clearance of topotecan was 824 +/- 154 ml min-1 (range 535-1068 ml min(-1)). The AUC ratio of topotecan and the lactone ring-opened hydrolysis product (hydroxy acid) was of the same order after oral (0.34-1.13) and i.v. (0.47-0.98) administration. The bioavailability of topotecan after oral administration illustrates significant systemic exposure to the drug which may enable chronic oral treatment.Keywords
This publication has 15 references indexed in Scilit:
- Pediatric phase I trial and pharmacokinetic study of topotecan administered as a 24-hour continuous infusion.1993
- Activity of Topotecan, a New Topoisomerase I Inhibitor, Against Human Tumor Colony-Forming Units In VitroJNCI Journal of the National Cancer Institute, 1992
- A phase I clinical and pharmacokinetic study of the topoisomerase I inhibitor topotecan (SK&F 104864) given as an intravenous bolus every 21 daysAnti-Cancer Drugs, 1992
- Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor.Journal of Clinical Oncology, 1992
- Evaluation of 9-dimethylaminomethyl-10-hydroxycamptothecin against xenografts derived from adult and childhood solid tumorsCancer Chemotherapy and Pharmacology, 1992
- Synthesis of water-soluble (aminoalkyl)camptothecin analogs: inhibition of topoisomerase I and antitumor activityJournal of Medicinal Chemistry, 1991
- High-performance liquid chromatographic analysis of the new antitumour drug SK&F 104864-A (NSC 609699) in plasmaJournal of Pharmaceutical and Biomedical Analysis, 1990
- DNA Topoisomerase I—Targeted Chemotherapy of Human Colon Cancer in XenograftsScience, 1989
- Pharmacokinetic parameter estimates from several least squares procedures: Superiority of extended least squaresJournal of Pharmacokinetics and Biopharmaceutics, 1985
- Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equationsJournal of Pharmacokinetics and Biopharmaceutics, 1978