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A
mechanistic mathematical model of temozolomide myelosuppression in children with
high-grade gliomas
Panetta JC, Kirstein MN, Gajjar AJ, Nair G, Fouladi M, Stewart CF
Department of Pharmaceutical Sciences, St. Jude Children's
Research Hospital, 332 North Lauderdale St., Memphis, TN 38105-2794, USA.
Temozolomide (TMZ) is currently being evaluated for the treatment of high-grade
gliomas in children.
Myelosuppression (the suppression of bone marrow activity) is the dose-limiting
toxicity for TMZ in adults and children.
Empirical methods (i.e. relations between the percent change in absolute
neutrophil count (ANC) and the area under the plasma concentration curve (AUC)
of TMZ or its active metabolite MTIC) showed poor results when attempting to
describe myelosuppression from serial data derived during TMZ therapy in a Phase
II study of children with high-grade glioma.
Therefore, to improve our understanding of the myelosuppressive effects of TMZ
and MTIC in children we developed a mechanistic mathematical model.
The model describes the progression of neutrophils from their production in the
bone marrow to their release in the plasma.
Included in the model are the feedback effects of granulocyte colony stimulating
factor (G-CSF), which stimulates neutrophil production when there is a decrease
in circulating neutrophils.
The model is fit to serial ANC measurements obtained after TMZ dosing and it is
able to explain, among other things, the lag in ANC reduction following a dose
of TMZ, the ANC nadir, and the 'rebound effect' observed where the ANC recovers
to levels greater than that observed pre-TMZ dose.
This model will be useful for the prospective design of clinical trials of TMZ
in children with cancer.
PMID: 14527745 [PubMed - indexed for MEDLINE]
Source:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14527745
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