Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 18, Issue 3, pp 247–251 | Cite as

Pharmacokinetics and tissue disposition of the biological response modifier BAY i 7433 (copovithane) in patients with cancer

  • Michael G. Rosenblum
  • Gabriel N. Hortobagyi
Original Articles Pharmacokinetics Biological Response Modifier

Summary

Copovithane is an uncharged, water-soluble, synthetic polymer with an average molecular weight of 5800 daltons. It demonstrates antitumor activity in vivo against a variety of tumors in animal models but is inactive in vitro. This agent has been found to have immunorestorative activity in man. In concert with its phase I clinical trial, copovithane concentrations were analyzed by HPLC in plasma, urine, and autopsy and in tumor biopsy specimens obtained from patients. Copovithane was cleared from plasma biphasically with a mean t1/2α of 11.1±4 min and a t1/2β of 246±78 min at the dose of 1 g/m2, while the plasma half-lives increased to 57.7±12 and 718±149 for the alpha and beta phases, respectively, at the 10 g/m2 dose, demonstrating clear, dose-dependent pharmacokinetics. There were no significant differences between dose 1 and dose 4 pharmacokinetics. The apparent volume of distribution (Vd) was 14.5±1. at the 1 g/m2 dose and increased to 73 1. at the 33 g/m2 dose. The calculated mean clearance rate for copovithane in plasma was between 2.4 and 5.4 mg/kg x min and did not appear to be dose-dependent. The urinary excretion of copovithane was approximately 5% of the administered dose over 120 h at the 1 g/m2 dose and decreased to 1% at the 33 g/m2 dose. In seven tumor biopsy samples, concentrations of drug in tumor varied from 1- to 1000-fold higher than that found in concurrent plasma samples. In three autopsy samples, the highest concentrations were found in kidney, intestine, and liver, in decreasing order. These studies show that copovithane exhibits dose-dependent changes in pharmacokinetics at doses between 1 and 33 g/m2. However, copovithane does penetrate well to tumor tissues, achieving high tumor/plasma ratios. In addition, copovithane concentrations were highest in kidney tissue, which may be a site for potential organ toxicity.

Keywords

Average Molecular Weight Clearance Rate Biopsy Sample Synthetic Polymer Response Modifier 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Conney A (1971) Environmental factors influencing drug metabolism In Fundamentals of drug metabolism and drug disposition. Waverly, Baltimore P 253Google Scholar
  2. 2.
    Gutterman JU, Rosenblum MG, Rios A, Fritsche HA, Quesada JR (1984) Pharmacokinetic study of partially pure gammainterferon in cancer patients. Cancer Res 44: 4164Google Scholar
  3. 3.
    Rosenblum MG, Hortobagyi GN, Wingender W, Hersh EM (1984) Analysis of the antitumor agent BAYi 7433 (copovithane) in plasma and urine by high performance liquid chromatography. J Liquid Chromatogr 7: 159Google Scholar
  4. 4.
    Schlumberger HD (1981) BAYi 7433 A synthetic polymer with antitumor activity. In Augmenting agents in cancer therapy. Raven, New York, p 373Google Scholar

Copyright information

© Springer-Verlag 1986

Authors and Affiliations

  • Michael G. Rosenblum
    • 1
    • 2
  • Gabriel N. Hortobagyi
    • 3
  1. 1.Department of Clinical ImmunologyThe University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor InstituteHoustonUSA
  2. 2.Department of Biological TherapyThe University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor InstituteHoustonUSA
  3. 3.Department of Medical OncologyThe University of Texas System Cancer, M. D. Anderson Hospital and Tumor InstituteHoustonUSA

Personalised recommendations