Validation of a therapeutic drug monitoring strategy for thiotepa in a high-dose chemotherapy regimen

Citation
Adr. Huitema et al., Validation of a therapeutic drug monitoring strategy for thiotepa in a high-dose chemotherapy regimen, THER DRUG M, 23(6), 2001, pp. 650-657
Citations number
19
Categorie Soggetti
Pharmacology,"Pharmacology & Toxicology
Journal title
THERAPEUTIC DRUG MONITORING
ISSN journal
01634356 → ACNP
Volume
23
Issue
6
Year of publication
2001
Pages
650 - 657
Database
ISI
SICI code
0163-4356(200112)23:6<650:VOATDM>2.0.ZU;2-H
Abstract
Thiotepa is an alkylating agent widely used in high-dose chemotherapy. The pharmacokinetics of thiotepa and its main metabolite tepa show a wide inter patient variability, which may be responsible for the interpatient variabil ity in toxicity. The aim of this study was to develop and validate a pharma cokinetically guided doing strategy with the sum of the thiotepa and tepa a rea under the concentration-time curve (AUC) as the target parameter. A tot al of 46 patients received 77 courses of chemotherapy with thiotepa (80-120 mg/m(2) per day) divided into two daily 30-minute infusions in combination with cyclophosphamide and carboplatin. Patients received up to three cours es of chemotherapy. The interpatient, course-to-course, day-to-day, and res idual variability in the pharmacokinetics of thiotepa and tepa were estimat ed with a population analysis with the software program NONMEM. The planned strategy consisted of the collection of blood samples on day 1 and either day 3 or day 4 of each 4-day course. The thiotepa dose was planned to be ad justed on day 3 of each course and before the start of a new course on the basis of Bayesian predictions of the pharmacokinetics with data of day 1 an d/or the possible previous course. The prediction procedure was validated b y dividing the dataset into an index and validation set. The Bayesian predi ctions of the validation set were compared with true AUC values generated w ith individual fits of each course. The performance of the complete strateg y was tested with a simulation procedure in 1,000 patients. Interpatient va riability and course-to-course variability were in the same order (+/- 20%) ; day-to-day variability was less (+/- 15%). The sampling strategy resulted in predictions of the AUC without bias with acceptable precision (+/- 20%) . The simulation showed that variability in exposure was effectively decrea sed by the dosing strategy. This strategy resulted in a reduction in the va riability of the exposure to thiotepa and tepa and can be implemented in a clinical study.