Topotecan

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Abstract
The topoisomerase I inhibitor topotecan has shown antitumour activity against a variety of tumour types in vitro and in vivo. Topotecan in combination with drugs that induce DNA damage generally results in synergistic killing of tumour cells in vitro. As the activity of topotecan is related to exposure time, the drug is administered by intravenous infusion either continuously or once daily over a 30-minute period for several consecutive days. A 30-minute infusion of topotecan 1.5 mg/m2 on 5 consecutive days every 3 weeks produced response rates of up to ≈20% in patients with advanced ovarian cancer who had failed to respond to platinum-based regimens or relapsed after initial response to such regimens. No significant differences in efficacy were apparent between topotecan and paclitaxel in a phase III study in patients with recurrent ovarian cancer, although a trend in favour of topotecan was evident for all major efficacy parameters. Non-cumulative myelosuppression, including neutropenia, thrombocytopenia and anaemia, is the dose-limiting toxicity associated with topotecan. Myelosuppression was significantly more common with topotecan than with paclitaxel in a single comparative study. Non-haematological adverse events in topotecan recipients are generally mild and include alopecia, nausea, vomiting, and other gastrointestinal problems. Thus, topotecan has modest efficacy in the treatment of recurrent advanced ovarian cancer, with clinical activity similar to that of paclitaxel in a large randomised phase III study in this setting. Combinations of paclitaxel and a platinum compound are being used increasingly for first-line therapy, although relapse rates remain significant. Topotecan is therefore a suitable second-line option, providing antitumour response for some patients whose disease has relapsed after, or is refractory to, platinum-based therapy. Its wider potential when used either alone or in combination regimens should become clearer from ongoing studies. Topotecan is a water soluble semisynthetic derivative of camptothecin which exerts an antineoplastic effect by inhibiting the nuclear enzyme topoisomerase I. The cytotoxicity of topotecan in vitro is related to exposure time and is significantly greater with continuous exposure to low concentrations of the drug than brief exposure to higher concentrations. Topotecan exhibited some selectivity for human ovarian tumour cells in vitro. Intraperitoneal administration of topotecan 10 mg/kg once every 4 days increased median survival time in mice with an intraperitoneal human ovarian cancer xenograft and was more effective than doxorubicin 5 mg/kg, cisplatin 4 or 6 mg/kg and carboplatin 60 mg/kg. The degree of enhancement of cytotoxicity with combinations of topotecan and a variety of other antineoplastic drugs depended on tumour type, duration of exposure, drug concentrations, calculation methods and drug sequence. The addition of drugs that induce DNA damage, such as cisplatin, carmustine or melphalan, to topotecan generally resulted in synergistic killing of hamster V79 cells and a variety of human cancer cell lines. Classical multidrug-resistant Chinese hamster ovary cells expressing a high level of P-glycoprotein were modestly cross-resistant to topotecan and other camptothecin derivatives. Topotecan exhibited similar activity against susceptible and multidrug-resistant murine leukaemia in vivo. Topotecan, like other camptothecin derivatives, is present in plasma as an active closed-ring lactone and an inactive open-ring form (carboxylate). After intravenous infusion of topotecan 0.5 to 22.5 mg/m2 /day over a 30-minute period, there was a linear relationship between dose and mean peak plasma concentrations and the area under the plasma concentration-time curve for the lactone. During 24-hour infusion steady-state concentrations of the carboxylated form were 1.5 to 1.9 times those of the lactone in adults. Protein binding of topotecan is low (6.6 to 31.3%) and apparent volume of distribution (Vd) has varied between 15 and 86.1 L/m. Reported mean total plasma clearance (CL) rates were between 17.2 and 69.5 L/h/m2 for the lactone and between 6.5 and 30 L/h/m2 for total topotecan. 24-hour urinary recovery rates were between 20.4 and 41.6%. Mean elimination half-lives were between 1.78 and 4.7 hours. In patients with impaired renal function (creatinine clearance 1500 cells/μl and a platelet count of >100 000/μl. Dosage should be reduced to 0.75 mg/m2 /day in patients with moderate renal impairment [creatinine clearance <40 ml/min (2.4 L/h)].

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