Phase I and pharmacokinetic trial of intraperitoneal etoposide in combination with the multidrug-resistance-modulating agent dipyridamole.

Abstract

Dipyridamole synergistically enhances the sensitivity of human ovarian carcinoma cells to etoposide in vitro. We conducted a phase I trial to investigate the feasibility of using dipyridamole to selectively increase the sensitivity to etoposide of tumors confined to the peritoneal cavity. Etoposide and dipyridamole were administered as a continuous 72-hour intraperitoneal infusion to 16 patients. The maximum tolerated dose of etoposide was 175 mg/m2 per day when administered with dipyridamole at a fixed dose of 24 mg/m2 per day. Dose-limiting toxic effects were leukopenia and thrombocytopenia. No other major toxic effects were observed. The free peritoneal etoposide and dipyridamole concentrations varied with the etoposide dose rate, reaching 218.9 and 25.3 microM, respectively, at an etoposide dose rate of 175 mg/m2 per day. The free etoposide and dipyridamole concentrations attained were well within the range needed for synergistic interaction.