Pharmacokinetics and Pharmacodynamics of High Dose Methotrexate in Children with Acute Lymphoblastic Leukemia and down Syndrome: a Case Cohort Study
| Autor: | Christian M. Zwaan, Rob Pieters, M. Van Den Heuvel, E. R. Van Wering, R. Mathot, T. Buitenkamp, A. Vulto, Anjo J.P. Veerman |
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| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_specialty
education.field_of_study business.industry Immunology Population Cell Biology Hematology medicine.disease Biochemistry NONMEM Surgery Leukemia Pharmacokinetics Internal medicine Pharmacodynamics Acute lymphocytic leukemia medicine Methotrexate Dosing education business medicine.drug |
| Zdroj: | Blood. 112:1626-1626 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Children with Down Syndrome (DS) have an increased risk of developing leukemia, including both acute myeloid, as well as acute lymphoblastic leukemia (DS-ALL). DS ALL patients have a poorer tolerance for high-dose methotrexate (HD-MTX), which is one of the key components of ALL treatment. There are no specific dosing guidelines for HD-MTX in DS-ALL. As a result doses are frequently reduced. In this study the pharmacokinetics (PK) and pharmacodynamics of HD-MTX were studied retrospectively in DS-ALL patients in order to develop specific dosing guidelines. Only one study addressed MTX-pharmacokinetics (PK) in DS children (Garre et al, J Pediatrics 1987). They found that median MTX plasma concentrations, 42 hours after infusion, were significantly higher in 5 DS-ALL patients compared to 3 non-DS controls. A retrospective case-cohort study was performed with DS-ALL patients enrolled in treatment protocols DCOG ALL-8, -9 or -10 in 8 Dutch medical centers during the period Nov 1991-Dec 2006. MTX dosages varied from 2.0–5.0 gr/m2 in the different treatment protocols. Forty-four DS and 87 non DS-ALL patients were included. The latter were matched for treatment protocol, sex and body surface area. All DS-ALL patients had B-cell-precursor ALL, and the median diagnostic WBC was 8,8*109/L. MTX serum levels and toxicity data were collected from patient files. Toxicity was graded according to CTCAE v3.0. Population PK-models were fitted to data from all individuals simultaneously, using non-linear mixed effect modeling (NONMEM). The PK of MTX was described according to a two-compartment model with a first order elimination from the central compartment. A total of 468 HD-MTX courses were given to 44 DS and 87 non-DS children. In 20% of the DS-ALL patients doses were reduced, comprising 26/152 (17.1%) of MTX courses. In 18/26 courses, dose-reduction was electively initiated from the 1st course onwards, whereas in 8/26 courses dose-reductions were applied from the 2nd course onwards because of documented toxicity in the 1st course. Dose reductions did not occur in non DS-ALL patients (p |
| Databáze: | OpenAIRE |
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