Pharmacologic study of etoposide and cisplatin by the intraperitoneal route

Based on the previous demonstration of a high peritoneal-to-plasma ratio of drug exposure for intraperitoneal (IP) etoposide, the authors performed a clinical/pharmacokinetic trial of etoposide (600 mg/m2) in combination with cisplatin (100 mg/m2). The drugs were administered concurrently IP, and allowed to dwell for 4 hours, after which the peritoneum was drained. Six patients received 13 cycles of treatment. Grade 4 neutropenia occurred in three patients; toxicity was otherwise moderate. Plasma etoposide concentrations reached a peak at 4.2 +/- 2.5 hours and declined exponentially with a terminal half-life of 9.5 +/- 3.6 hours. Peritoneal etoposide concentrations declined monoexponentially with a half-life of 3.7 +/- 2.6 hour. The calculated peritoneal-to-plasma ratio of unbound etoposide was 35. The plasma and peritoneal half-lives of ultrafilterable cisplatin were 21.7 +/- 14.1 hours and 1.8 +/- 0.7 hours, respectively. The peritoneal/plasma area under curve AUC ratio was 18.3. These pharmacokinetic indices for both drugs are consistent with those obtained with the use of each drug as a single agent. Thus, the concomitant use of one does not alter the pharmacokinetic activity of the other. The high AUC ratios support the further clinical development of these drugs in combination in the intraperitoneal setting.