Thioguanine pharmacokinetics in induction therapy of children with acute myeloid leukemia.

Abstract

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.

• Authors: Josefine Palle, Palle Josefine, Britt-Marie Frost, Frost Britt-Marie, Curt Petersson, Petersson Curt, Henrik Hasle, Hasle Henrik, Marit Hellebostad, Hellebostad Marit, Jukka Kanerva, Kanerva Jukka, Kjeld Schmiegelow, Schmiegelow Kjeld, Gudmar Lönnerholm, Lönnerholm Gudmar, Nordic Society for Paediatric Haematology and Oncology
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 20 Issue 1 Pg. 7-14 (Jan 2009) ISSN: 1473-5741 [Electronic] England
• PMID: 19342996 (Publication Type: Clinical Trial, Comparative Study, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Guanine Nucleotides
• Thionucleotides
• Cytarabine
• 6-thioguanylic acid
• Etoposide
• Doxorubicin
• Thioguanine

Topics

• Administration, Oral
• Adolescent
• Antimetabolites, Antineoplastic (administration & dosage, blood, pharmacokinetics)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Child
• Child, Preschool
• Cytarabine (administration & dosage)
• Down Syndrome (blood, complications)
• Doxorubicin (administration & dosage)
• Drug Administration Schedule
• Drug Monitoring (methods)
• Erythrocytes (metabolism)
• Etoposide (administration & dosage)
• Female
• Guanine Nucleotides (blood)
• Humans
• Infant
• Infusions, Intravenous
• Leukemia, Myeloid, Acute (blood, complications, drug therapy)
• Male
• Registries
• Scandinavian and Nordic Countries
• Thioguanine (administration & dosage, blood, pharmacokinetics)
• Thionucleotides (blood)
• Treatment Outcome