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Schedule-dependent Activity of Topotecan in OVCAR-3 Ovarian Carcinoma Xenograft

Pharmacokinetic and Pharmacodynamic Evaluation

Groupe de Pharmacologie clinique et expérimentale (EA 3035), Institut Claudius Regaud, 31052 Toulouse [S. G., A. M., E. C., I. H., R. B., P. C], and Université Paul Sabatier, 31062 Toulouse [S. G., A. M., E. C., R. B.], France

Topotecan is a topoisomerase (Topo) I inhibitor used in ovarian carcinoma chemotherapy. Topo I inhibitors are thought to be more cytotoxic using protracted schedules of administration. We tested this hypothesis on a preclinical model: human ovarian carcinoma OVCAR-3 implanted i.p. Nude mice were treated i.p. with a total dose of topotecan of 12.5 mg/kg delivered in 1, 5, 10, 20, 40, or 80 daily injections. The toxicity was maximal when the total dose was delivered within 5 and 10 days of treatment. However, the efficacy was the greatest (all of the mice cured) in the 20-day schedule using 0.625 mg/kg/day, hence, making this latter schedule the most efficient without any major toxicity. A pharmacokinetic study was conducted to identify parameters related to the efficacy and toxicity of topotecan in our model. The use of a population pharmacokinetic approach allowed us to define a therapeutic window: maintaining plasma concentrations above 0.2 µM for >10 h was necessary for an optimal antitumor effect and avoiding plasma concentrations >0.7 µM allowed a manageable toxicity. Finally, Topo I activity was monitored in ascites from animals treated with different topotecan administration schedules. The optimal schedule defined above allowed for sustained inhibition of Topo I activity associated with a greater antitumor activity. These in vivo data constitute a rationale for clinical studies testing this type of administration.

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