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- Title
Development of a pharmacokinetic limited sampling model for temozolomide and its active metabolite MTIC.
- Authors
Kirstein, Mark N.; Panetta, John C.; Gajjar, Amar; Nair, Geeta; Iacono, Lisa; Freeman III, Burgess B.; Stewart, Clinton F.; Iacono, Lisa C; Freeman, Burgess B 3rd
- Abstract
<bold>Purpose: </bold>To develop a pharmacokinetic limited sampling model (LSM) for temozolomide and its metabolite MTIC in infants and children.<bold>Methods: </bold>LSMs consisting of either two or four samples were determined using a modification of the D-optimality algorithm. This accounted for prior distribution of temozolomide and MTIC pharmacokinetic parameters based on full pharmacokinetic sampling from 38 patients with 120 pharmacokinetic studies (dosage range 145-200 mg/m(2) per day orally). Accuracy and bias of each LSM were determined relative to the full sampling method. We also assessed the predictive performance of the LSMs using Monte-Carlo simulations.<bold>Results: </bold>The four strategies generated from the D-optimality algorithm were as follows: LSM 1=0.25, 1.25, and 3 h; LSM 2=0.25, 1.25, and 6 h; LSM 3=0.25, 0.5, 1.25, and 3 h; LSM 4=0.25, 0.5, 1.25, and 6 h. LSM 2 demonstrated the best combination of low bias [0.1% (-8.9%, 11%) and 11% (4.3%, 15%)] and high accuracy [-1.0% (-12%, 24%) and 14% (7.9%, 37%)] for temozolomide clearance and MTIC AUC, respectively. Furthermore, adding a fourth sample (e.g., LSM 4) did not substantially decrease the bias or increase the accuracy for temozolomide clearance or MTIC AUC. Results from Monte-Carlo simulations also revealed that LSM 2 had the best combination of lowest bias (0.1+/-6.1% and -0.8+/-6.5%), and the highest accuracy (4.5+/-4.1% and 5.0+/-4.3%) for temozolomide clearance and MTIC apparent clearance, respectively.<bold>Conclusions: </bold>Using data derived from our population analysis, the sampling times for a limited sample pharmacokinetic model for temozolomide and MTIC in children are prior to the temozolomide dose, and 15 min, 1.25 h and 6 h after the dose.
- Subjects
PHARMACOKINETICS; PHARMACOLOGY; INFANTS; CHILDREN; ALGORITHMS; MONTE Carlo method; MATHEMATICAL models; NUMERICAL analysis; ANTINEOPLASTIC agents; BIOTRANSFORMATION (Metabolism); CENTRAL nervous system tumors; CLINICAL trials; COMPARATIVE studies; RESEARCH methodology; MEDICAL cooperation; RESEARCH; SYSTEM analysis; EVALUATION research; DACARBAZINE
- Publication
Cancer Chemotherapy & Pharmacology, 2005, Vol 55, Issue 5, p433
- ISSN
0344-5704
- Publication type
journal article
- DOI
10.1007/s00280-004-0896-9