Pharmacokinetics of intraperitoneal mitomycin C.
The favorable pharmacokinetics of MMC, used during intraperitoneal chemotherapy, has been reported in several studies [11-19]. A major safety issue in studies using intraperitoneal chemotherapy perfusion is the resulting systemic drug exposure. The AUCplasma is determined by the dose, the clearance, and the fraction absorbed from the peritoneal cavity. The reported mean plasma peak concentrations are about one-third of the systemic exposure following a therapeutic dose of MMC given by intravenous administration [30]. The best method to quantify the exposure to MMC are the time concentration profiles (AUC). Because MMC can still be found in plasma the day after intraperitoneal administration, the AUC0-90 is an underestimate of the real AUC; extrapolation to infinity gives the most reliable AUCplasma value. In our series the AUCplasma is about half the AUCplasma when given a therapeutic dose MMC intravenously [30]. What is the best dose in intraperitoneal chemotherapy perfusion? The ideal amount of MMC should include a high AUCperfusate, a high AUCplasma and an acceptable systemic toxicity. In our series grade III/IV leucopenia was observed in 28% patients. We find this rather high percentage acceptable as the problem has proved to be transient, and we have experienced no toxic deaths in recent years. In a phase I study it was estimated that a dose of 25 mg/m2 would result in approximately 10% of grade III/IV leucopenia [20]. Our data indicate that dosing based on body surface area is rational and reliable. The variation between individuals is low. Dosing based on a fixed concentration per liter perfusion fluid is probably more liable to have unforeseen variations, given the fact that we deal with linear pharmacokinetics of MMC [20]. As represented in Fig. 3, the dose of MMC can best be administered in three divided doses, resulting in the more equal exposure of peritoneal structures to MMC during the perfusion. It must be emphasized that our findings only hold true for the perfusion system as used in The Netherlands Cancer Institute. This involves a semi-open abdomen, basic perfusate volume of 3 L, perfusion rate of 1 L/min, abdominal temperature of 40 degrees C, 90 minutes of perfusion, and three drug additions (50% at t = 0, 25% at t = 30 and t = 60 minutes). The differences in perfusion techniques make comparisons of published pharmacokinetics data difficult. Cautions comparison suggest that most groups are dosing far below the maximal tolerated dose. We assume that there is a dose-effect relation for MMC. This means that obtaining a maximal safe dose is important to get maximal results. It seems that better dosing of intraperitoneal MMC can still improve results. The pharmacokinetics of intraperitoneal MMC can, however, be influenced by many details. Open or closed perfusion for instance may make some essential differences. It is therefore important that each treatment group performs its own pharmacokinetics studies on intraperitoneal MMC to achieve the optimal dose method for their chemotherapy perfusion setting. In conclusion, the major advantage of intraperitoneal chemotherapy is the regional dose intensity provided. Following intraperitoneal MMC administration, the affected peritoneal surface is exposed to high concentrations while the systemic toxicity is limited. Comparative analyses on MMC pharmacokinetics are difficult to perform because the diversity of treatment techniques. We recommend administration of MMC, divided in three drug additions, based on BSA.