Phase I Trials and Pharmacokinetic Studies of Intraperitoneal Cisplatin, Melphalan, Methotrexate, and Cytarabine

  • Stephen B. Howell
  • Craig E. Pfeifle
  • Maurie Markman
Part of the Developments in Oncology book series (DION, volume 26)

Abstract

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.

Keywords

Toxicity Hydrate Platinum Creatinine Methotrexate 

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References

  1. 1.
    Dedrick, R.L., Myers, C.E., Bungay, P.M., and DeVita, V.T. Jr. Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian cancer. Cancer Treatment Reports 62: 1–9, 1978.PubMedGoogle Scholar
  2. 2.
    Howell, S.B., Pfeifle, C.E., Wung, W.E., Olshen, R.A., Lucas, W.E., Yon, J.L., and Green, M. Intraperitoneal Cisplatin with Systemic Thiosulfate Protection. Annals of Internal Medicine 97: 845–851, 1982.PubMedGoogle Scholar
  3. 3.
    Howell, S.B., Pfeifle, C.E., Wung, W.E., Olshen, R.A. Intraperitoneal cisplatin with systemic thiosulfate protection. Cancer Research 43: 1426–1431, 1983.PubMedGoogle Scholar
  4. 4.
    Campbell, T.N., Howell, S.B., Pfeifle, C.E., Wung, W.E., Bookstein, J. Pharmacokinetics of intra-arterial cisplatin in man. Cancer Research, in press, 1984.Google Scholar
  5. 5.
    Woliver, T., Felthouse, R., Markman, M., Pfeifle, C.E., Howell, S.B. Phase I trial of intravenous cisplatin (DDP) with sodium thiosulfate protection. Proc. Am. Assoc. Cancer Res. 24: 132, 1983.Google Scholar
  6. 6.
    Shea, M., Koziol, J.A., Howell, S.B. Human pharmacokinetics of sodium thiosulfate, a neutralizing agent for cisplatin. Clinical Pharmacol, and Therap., in press, 1983.Google Scholar
  7. 7.
    Pfeifle, C.E., Howell, S.B., Olshen, R.A. Intraperitoneal (I.P.) melphalan (L–PAM): a phase I study. Am. Soc. Clin. Pharmacol. Therap. 33: 223, 1983.Google Scholar
  8. 8.
    Howell, S.B., Chu, B.C.F., Wung, W., Metha, B., Mendelsohn, J. Long duration intracavitary infusion of methotrexate with systemic leucovorin protection in patients with malignant effusions. J. Clin. Invest. 67: 1167–1170, 1981.CrossRefGoogle Scholar
  9. 9.
    King, M.E., Smith, A., Young, B., and Howell, S.B. Modulation of cytarabine uptake and toxicity by dipyridamole. Cancer Treatment Reports, in press, 1984.Google Scholar

Copyright information

© Martinus Nijhoff Publishers, Boston 1984

Authors and Affiliations

  • Stephen B. Howell
    • 1
  • Craig E. Pfeifle
    • 1
  • Maurie Markman
    • 1
  1. 1.Department of Medicine, Cancer Center, and General Clinical Research CenterUniversity of CaliforniaSan Diego, La JollaUSA

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