A pediatric phase I and pharmacokinetic study of spirohydantoin mustard.
A pediatric Phase I and pharmacokinetic study of the lipophilic alkylating agent spirohydantoin mustard (SHM) was conducted in 23 patients. The dose-limiting toxicity of SHM was neurological with disorientation, delirium, or hallucinations occurring in 9 of 23 patients. These symptoms were partially reversible and preventable with physostigmine. In 17 patients who were evaluable for response to treatment (14 of whom had central nervous system malignancies), no objective tumor responses were observed. Pharmacokinetic evaluation of SHM revealed a t1/2 alpha of 1.7 +/- 0.7 min, t1/2 beta of 16 +/- 8.3 min, and total body clearance of 2134 +/- 735 ml/min/m2. Measureable peak plasma levels were less than 40% of that which produces cytotoxicity in vitro against monolayer cultures of rat 9L brain tumor. Over 90% of SHM was protein bound, greatly limiting the free drug available for central nervous system penetration. SHM cerebrospinal fluid to plasma ratios were less than 0.047. The above suggests that in spite of its lipophilicity, SHM may not reach clinically significant levels in the central nervous system at clinically tolerable doses.
Heideman
R L
RL
Pediatric Branch, National Cancer Institute, Bethesda, Maryland 20892.
Kelley
J A
JA
Packer
R J
RJ
Reaman
G H
GH
Roth
J S
JS
Balis
F
F
Ettinger
L J
LJ
Doherty
K M
KM
Jeffries
S L
SL
Poplack
D G
DG
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D006827:Hydantoins / Q000009:adverse effects* / Q000493:pharmacokinetics; D008297:Male; D009420:Nervous System / Q000187:drug effects; D009588:Nitrogen Mustard Compounds / Q000009:adverse effects* / Q000493:pharmacokinetics; D010830:Physostigmine / Q000627:therapeutic use; D011485:Protein Binding
D000970:Antineoplastic Agents; D006827:Hydantoins; D009588:Nitrogen Mustard Compounds; D010830:Physostigmine; C015511:spiromustine