Development of a pharmacokinetic limited sampling model for temozolomide and its active metabolite MTIC.
OBJECTIVE
To develop a pharmacokinetic limited sampling model (LSM) for temozolomide and its metabolite MTIC in infants and children.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Kirstein
Mark N
MN
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA.
Panetta
John C
JC
Gajjar
Amar
A
Nair
Geeta
G
Iacono
Lisa C
LC
Freeman
Burgess B
BB
Stewart
Clinton F
CF
D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D016543:Central Nervous System Neoplasms / Q000378:metabolism*; D002648:Child; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D007223:Infant; D008657:Metabolic Clearance Rate; D009010:Monte Carlo Method; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; C010243:5-(3-methyl-1-triazeno)imidazole-4-carboxamide; D000077204:Temozolomide