Pharmacokinetic study of cystemustine, administered on a weekly schedule in cancer patients.

Abstract

BACKGROUND:

Cystemustine is a chloroethylnitrosourea mostly active in humans against glioma and melanoma. The present report describes the results of a new phase I trial with cystemustine administered on a weekly schedule. The pharmacokinetic and pharmacodynamic properties of cystemustine were investigated.

PATIENTS AND METHODS:

Forty-three patients entered this study. Cystemustine was administered at dose levels ranging from 30 to 60 mg/m2. The drug was given on days 1, 8, 15 and 22, followed by a 4-week rest period.

RESULTS:

Thrombocytopenia was the dose-limiting toxicity and appeared to be reversible, but probably cumulative. This toxicity appeared dose-related, both in frequency and severity. The maximum tolerated dose was 60 mg/m2. Nonhematological toxicity was generally mild. Three partial responses were observed at dose levels of 50 and 60 mg/m2. Pharmacokinetics analysis showed mono- or biphasic cystemustine blood disposition with a mean a half-life of 4 min and mean terminal half-life of 49 min.

CONCLUSIONS:

There was a clear linear relationship between the area under the blood drug concentration-time curve (AUC) and the dose of cystemustine (P < 0.001). There was also a significant relationship between the AUC and the toxic effects of cystemustine on platelets, granulocytes and leukocytes (P < 0.001). A reasonable starting dose for phase II studies is 40 mg/m2, with dose escalation based on blood cell counts.

• Authors: E Cellarier, C Terret, P Labarre, R Ouabdesselam, H Curé, C Marchenay, J C Maurizis, J C Madelmont, P Cholle, J P Armand
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 13 Issue 5 Pg. 760-9 (May 2002) ISSN: 0923-7534 [Print] England
• PMID: 12075746 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nitrosourea Compounds
• N'-(2-chloroethyl)-N-(2-(methylsulfonyl)ethyl)-N'-nitrosourea

Topics

• Adolescent
• Adult
• Aged
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Follow-Up Studies
• Humans
• Linear Models
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (diagnosis, drug therapy, mortality)
• Nitrosourea Compounds (administration & dosage, pharmacokinetics)
• Probability
• Survival Analysis
• Treatment Outcome