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
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.