Phase I Trials and Pharmacokinetic Studies of Intraperitoneal Cisplatin, Melphalan, Methotrexate, and Cytarabine
Phase I and pharmacokinetic studies of the intraperitoneal administration of cisplatin, melphalan, methotrexate, and cytarabine have been completed at the UCSD Cancer Center. For all four agents, there is a very large pharmacologic advantage to administration via the intraperitoneal route. The mean ratio of total drug exposure for the peritoneal cavity to plasma was 12.4 (range 2.9–37.4) for cisplatin, 65 (range 17–176) for melphalan, 92 (range 7–303) for methotrexate, and 570 (range 320–1000) for cytarabine. The dose-limiting toxicity for all four agents was systemic rather than local, and the dose administered into the peritoneal cavity could be escalated to the point where the amount of drug leaking into the sytemic circulation provided a total drug exposure for the plasma equivalent to that which could be obtained with intravenous injection. In the case of cisplatin, concurrent systemic administration of sodium thiosulfate provided excellent protection for the kidneys and permitted escalation of the total intraperitoneal cisplatin dose to 270 mg/m2. In the case of methotrexate and cytarabine, it was possible to maintain intraperitoneal concentrations well above the minimal cytotoxic level for ovarian carcinoma for a period of five days with acceptable systemic toxicity. The results indicate that these four drugs can be repeatedly administered into the peritoneal cavity and that this route of administration results in a very great pharmacologic advantage relative to systemic administration.
KeywordsToxicity Hydrate Platinum Creatinine Methotrexate
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