Regular Article

British Journal of Cancer (2001) 85, 1627–1633. doi:10.1054/bjoc.2001.2161 www.bjcancer.com
Published online 27 November 2001

A phase I and pharmacokinetic study of intraperitoneal topotecan

L S Hofstra1, A M E Bos1, E G E de Vries1, A G J van der Zee2, J H Beijnen3, H Rosing3, N H Mulder1, J G Aalders2 and P H B Willemse1

  1. 1Department of Medical, PO Box 30.001, Groningen, RB, 9700, The Netherlands
  2. 2Gynaecologic Oncology, University Hospital Groningen, PO Box 30.001, Groningen, RB, 9700, The Netherlands
  3. 3Department of Pharmacy and Pharmacology, Slotervaart Hospital, Louwesweg 6, Amsterdam, EC, 1066, The Netherlands

Received 27 November 2000; Revised 2 August 2001; Accepted 17 September 2001.

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Abstract

Purpose: To evaluate the feasibility and pharmacology of intraperitoneal (IP) topotecan. Patients and methods: Fifteen patients with recurrent ovarian cancer in a phase I trial were treated with escalating IP topotecan doses (5–30 mg/m2) for pharmacokinetic analysis. Results: Dose limiting toxicity (DLT) was acute hypotension, chills and fever at the 30 mg/m2 dose level. Haematological toxicity and abdominal pain were mild for all dose levels studied. Pharmacokinetics: Peak plasma levels of total topotecan were reached at 2.7 plusminus 1.1 h after IP instillation. The apparent Vss was 69.9 plusminus 25.4 L/m2, plasma clearance 13.4 plusminus 2.5 L/h/m2 and plasma T1/2 3.7 plusminus 1.3 h. The plasma AUC was correlated with the dose (R = 0.95, P < 0.01). The plasma AUC ratio of lactone versus total topotecan (lactone + carboxy-forms) increased with the dose from 16% to 55%, (R = 0.84, P < 0.01). Peritoneal total topotecan was cleared from the peritoneal cavity at 0.4 plusminus 0.3 L/h.m2 with a T1/2 = 2.7 plusminus 1.7 h. The mean peritoneal/plasma AUC ratio for total topotecan was 54 plusminus 34. Conclusion: A substantial dose of topotecan can be delivered by the IP route, achieving cytotoxic plasma levels of topotecan, with acceptable toxicity. The recommended dose for further phase II trials is 20 mg/m2 IP, which enables combination with active doses of other cytotoxic drugs, in view of its limited myelotoxicity when given by this route. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords:

intraperitoneal, topotecan, ovarian cancer, pharmacokinetics, phase I

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