Phase I and pharmacokinetic study of intraperitoneal thioTEPA in patients with ovarian cancer.
A total of 15 patients with residual ovarian cancer confined to the peritoneal cavity after first-line systemic chemotherapy were treated with triethylene-thiophosphoramide (thioTEPA) in a phase I study. A total of 50 courses of thioTEPA were given intraperitoneally in doses ranging from 30 to 80 mg/m2. The dose limiting toxicity was myelosuppression, which occurred at 80 mg/m2 and was frequently prolonged. Short-lived nausea and vomiting was easily controlled, and there was no local toxicity. Three patients remain free of disease progression at 6, 6 and 12 months. ThioTEPA concentrations were measured by gas chromatography. Peritoneal fluid concentrations declined rapidly in a first-order fashion, with a half-life of 0.96 +/- 0.1 h. A mean of 93% of the drug was absorbed during the 4-h dwell time. Peak plasma levels were achieved 30-60 min after drug instillation and were substantially lower than corresponding peritoneal levels. A pharmacokinetic advantage for intraperitoneal delivery was detected for peak drug concentration (24.9 +/- 8.5) and AUC (9.2 +/- 4.8). Based on this study, the recommended dose for intraperitoneal thioTEPA is 60 mg/m2 every 3-4 weeks. However, the rapid absorption of this drug from the peritoneum, secondary to thioTEPA's small molecular weight and lipophilic nature, suggests that it has only a limited role in intraperitoneal therapy.
CRC Department of Medical Oncology, University of Glasgow, Bearsden, UK.
C
C
Lewis
N
N
Lawson
E M
EM
Rankin
G
G
Morrison
A B
AB
MacLean
J
J
Cordiner
J
J
Cassidy
D J
DJ
Kerr
S B
SB
Kaye
D000328:Adult; D001201:Ascites / Q000517:prevention & control; D001202:Ascitic Fluid / Q000378:metabolism; D002408:Catheters, Indwelling; D004341:Drug Evaluation; D005260:Female; D006207:Half-Life; D006801:Humans; D007274:Injections, Intraperitoneal; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D010166:Palliative Care; D013852:Thiotepa / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
D013852:Thiotepa