A pharmacokinetic and clinical evaluation of thio-TEPA in combination with cisplatin as first-line chemotherapy for advanced epithelial ovarian carcinoma.
The purpose of the study was to explore the combination of thio-TEPA with cisplatin in first-line chemotherapy of epithelial ovarian cancer with special reference to pharmacokinetic and pharmacodynamic relationships. Ten women with advanced disease were included. Pharmacokinetics of thio-TEPA were similar to those in previous studies of single drug therapy with rapid first order elimination of the parent drug and substantial intra- and interindividual variation of the area under the concentration-time curve (AUC). No effects of the drug sequence or repeated treatments were seen on the pharmacokinetics of thio-TEPA, indicating no significant influence from the coadministration of cisplatin on the distribution, metabolism or excretion of thio-TEPA. Pharmacokinetic--pharmacodynamic relationships were less pronounced compared to previous studies, probably due to the influence from cisplatin. Prolongation of treatment intervals, dosage reduction, and withholding of thio-TEPA were required due to myelosuppression, which was the dominating toxicity. Non-hematological toxicity was moderate and easily manageable, cisplatin-related toxicity did not seem to be aggravated. Response rate based on CA 125 fluctuations was 80%, overall median survival was 18 months. In conclusion, the pharmacokinetics of thio-TEPA does not seem to be significantly influenced by concomitant administration of cisplatin in female patients. Manageable toxicity, largely restricted to myelosuppression, and high response rate justify further evaluation of the current regimen.
Hagen
B.
B
Section of Gynecologic Oncology, Department of Obstetrics & Gynecology, Trondheim University Hospital, Trondheim, Norway; Department of Pharmacology & Toxicology, Trondheim University Hospital, Trondheim, Norway.
Onsrud
M.
M
Dale
O.
O