Schedule-dependent activity of topotecan in OVCAR-3 ovarian carcinoma xenograft: Pharmacokinetic and pharmacodynamic evaluation

Topotecan is a topoisomerase (Topo) I inhibitor used in ovarian carcinoma c hemotherapy. Topo I inhibitors are thought to be more cytotoxic using protr acted schedules of administration. We tested this hypothesis on a preclinic al model: human ovarian carcinoma OVCAR-3 implanted i.p. Nude mice were tre ated i.p. with a total dose of topotecan of 12.5 mg/kg delivered in 1, 5, 1 0, 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 0.62 5 mg/kg/day, hence, making this latter schedule the most efficient without any major toxicity. A pharmacokinetic study was conducted to identify param eters related to the efficacy and toxicity of topotecan in our model. The u se of a population pharmacokinetic approach allowed us to define a therapeu tic window: maintaining plasma concentrations above 0.2 muM for > 10 h was necessary for an optimal antitumor effect and avoiding plasma concentration s >0.7 muM allowed a manageable toxicity. Finally, Topo I activity was moni tored in ascites from animals treated with different topotecan administrati on schedules. The optimal schedule defined above allowed for sustained inhi bition of Topo I activity associated with a greater antitumor activity. The se in vivo data constitute a rationale for clinical studies testing this ty pe of administration.