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


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.
Cellarier
E
E
Unité d'Oncothérapie Appliquée, Centre Jean Perrin, Clermont-Ferrand, France. recherche.clinique@cjp.u-clermont1.fr
Terret
C
C
Labarre
P
P
Ouabdesselam
R
R
Curé
H
H
Marchenay
C
C
Maurizis
J C
JC
Madelmont
J C
JC
Cholle
P
P
Armand
J P
JP
D000293:Adolescent; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016014:Linear Models; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D009607:Nitrosourea Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011336:Probability; D016019:Survival Analysis; D016896:Treatment Outcome
D009607:Nitrosourea Compounds; C051263:N'-(2-chloroethyl)-N-(2-(methylsulfonyl)ethyl)-N'-nitrosourea