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Thioguanine pharmacokinetics in induction therapy of children with acute myeloid leukemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Barnonkologisk forskning/Pfeifer)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Barnonkologisk forskning/Pfeifer)
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2009 (English)In: Anti-Cancer Drugs, ISSN 0959-4973, E-ISSN 1473-5741, Vol. 20, no 1, 7-14 p.Article in journal (Refereed) Published
Abstract [en]

We studied the pharmacokinetics of 6-thioguanine (6TG) in 50 children treated for newly diagnosed acute myeloid leukemia, four of them with Down syndrome (DS). They received oral 6TG 100 mg/m2 body surface area twice daily for 4 days. Etoposide, 100 mg/m2/24 h, and cytarabine, 200 mg/m2/24 h, were administered concomitantly by intravenous infusion. On day 5, doxorubicin 75 mg/m2 was given as an 8-h infusion. The concentration of thioguanine nucleotides (TGN) in erythrocytes, the active metabolites of 6TG, was determined by high-performance liquid chromatography. The mean TGN concentration from 72, 95, and 106-h samples was used as a measure of drug exposure for each individual. The median TGN concentration in non-DS children above 2 years of age was 2.30 micromol/mmol Hb (range 0.57-25.3). The TGN concentrations varied widely (30-fold) also after dose normalization. We found no correlation with demographic, clinical, or biochemical parameters, and differences in bioavailability might be the most important explanation to interpatient variability. Children with high TGN concentration tended to have longer treatment interval to the next course, but we found no correlation with our predefined parameters for clinical response, that is, remission and relapse rate. Therefore, 6TG does not seem to be a candidate for therapeutic drug monitoring by TGN measurement, at least not in the setting of short multidrug treatment courses. Children with DS had significantly higher TGN concentrations, indicating that dose reduction might be considered to reach the same drug exposure as in non-DS children.

Place, publisher, year, edition, pages
2009. Vol. 20, no 1, 7-14 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-121350DOI: 10.1097/CAD.0b013e32831bc086ISI: 000261760400002PubMedID: 19342996OAI: oai:DiVA.org:uu-121350DiVA: diva2:305001
Available from: 2010-03-22 Created: 2010-03-22 Last updated: 2013-06-14Bibliographically approved
In thesis
1. Optimizing Chemotherapy in Childhood Acute Myeloid Leukemia
Open this publication in new window or tab >>Optimizing Chemotherapy in Childhood Acute Myeloid Leukemia
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Despite major advances in our understanding of the biology of childhood acute myeloid leukemia (AML) and the development of new cytotoxic drugs, the prognosis of long-term survival is still only 60-65 %.

In the present research, we studied the pharmacokinetics of drugs used in the induction therapy of childhood AML and performed in vitro drug sensitivity testing of leukemic cells from children with AML.

The aims of the studies were to correlate the results of the analysis to biological and clinical parameters and to identify subgroups of AML with specific drug sensitivity profiles in order to better understand why treatment fails in some patients and how therapy may be improved.

Blood samples were analysed to study the pharmacokinetics of doxorubicin (n=41), etoposide (n=45) and 6-thioguanine (n=50). Doxorubicin plasma concentration and total body clearance were correlated to the effect of induction therapy, and doxorubicin plasma concentration was an independent factor for complete remission, both in univariate and multivariate analysis including sex, age, and white blood cell count at diagnosis. For etoposide and 6-thioguanine no correlation was found between pharmacokinetics and clinical effect. Children with Down syndrome (DS) tended to reach higher blood concentrations of etoposide and thioguanine nucleotides, indicating that dose reduction may be reasonable to reach the same drug exposure as in children without DS.

Leukemic cells from 201 children with newly diagnosed AML, 15 of whom had DS, were successfully analysed for in vitro drug sensitivity by the fluorometric microculture cytotoxicity assay (FMCA). We found that samples from children with DS were highly sensitive to most drugs used in AML treatment. In non-DS children, the t(9;11) samples were significantly more sensitive to cytarabine (p=0.03) and doxorubicin (p=0.035) than other samples. The findings might explain the very favorable outcome reported in children with DS and t(9;11)-positive AML. A specific drug resistance profile was found for several other genetic subgroups as well. A detailed study of MLL-rearranged leukemia showed that cellular drug sensitivity is correlated both to partner genes and cell lineage, findings that support the strategy of contemporary protocols to include high-dose cytarabine in the treatment of patients with MLL-rearrangement, both in AML and acute lymphoblastic leukemia (ALL).

Our results indicate that drug resistance and pharmacokinetic studies may yield important information regarding drug response in different sub-groups of childhood AML, helping us to optimize future chemotherapy in childhood AML.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 85 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 364
childhood, acute myeloid leukemia, drug resistance, pharmacokinetics, chromosomal abnormalities, Down syndrome, MLL-rearrangement, t(9;11)
National Category
urn:nbn:se:uu:diva-9189 (URN)978-91-554-7249-8 (ISBN)
Public defence
2008-09-26, Hedstrandsalen, Akademiska Sjukhuset, ingång 70, Uppsala, 13:15
Available from: 2008-09-04 Created: 2008-09-04 Last updated: 2013-06-14Bibliographically approved

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