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Vincristine in childhood leukemia: no pharmacokinetic rationale for dose reduction in adolescents
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Barnonkologisk forskning/Lönnerholm)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Barnonkologisk forskning/Lönnerholm)
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2003 (English)In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 92, no 5, 551-557 p.Article in journal (Refereed) Published
Abstract [en]

AIM: To investigate whether there is any pharmacokinetic rationale for the common practice of administering vincristine to adolescents at relatively lower doses than those to younger children.

METHODS: A total of 98 children, aged 1.3-17.3 y, with acute lymphoblastic leukaemia (ALL) were studied on day 1 of induction therapy. Plasma samples were drawn before and 10, 30, 360 and 1380 min after injection of vincristine 2.0 mg/m2 (maximum dose 2.0 mg) and analysed by high-performance liquid chromatography.

RESULTS: The median value (and range) for distribution half-life was 6.4 min (0.8-11.8), elimination half-life 1014 min (258-2570), volume of distribution 445 L/m2 (137-1241) and total body clearance 362 ml/min/m2 (134-2553). No correlation was found between age and any of these pharmacokinetic parameters. The area under the concentration time curve (AUC) was significantly correlated to age (p = 0.002; p - 0.31), as expected from the dosage of vincristine. The lower AUC in children with a body surface area > 1 m2, which is reached at 8-9 y of age, indicates that they received a less intense treatment because of the capping of the vincristine dose at 2.0 mg.

CONCLUSIONS: Vincristine pharmacokinetics were not age dependent in this paediatric population. Thus, we found no pharmacokinetic rationale for dose reduction in adolescents. The common practice of limiting the vincristine dose to 2.0 mg should be carefully reconsidered.

Place, publisher, year, edition, pages
2003. Vol. 92, no 5, 551-557 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-89997DOI: 10.1111/j.1651-2227.2003.tb02505.xPubMedID: 12839283OAI: oai:DiVA.org:uu-89997DiVA: diva2:161995
Available from: 2002-10-10 Created: 2002-10-10 Last updated: 2010-12-03Bibliographically approved
In thesis
1. Chemotherapy in Childhood Acute Lymphoblastic Leukemia: In vitro cellular drug resistance and pharmacokinetics
Open this publication in new window or tab >>Chemotherapy in Childhood Acute Lymphoblastic Leukemia: In vitro cellular drug resistance and pharmacokinetics
2002 (Swedish)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aims of the studies described in this thesis were to investigate the pharmacokinetics of and cellular resistance to chemotherapy as causes of treatment failure in childhood acute lymphoblastic leukemia (ALL).

Leukemic cells from 370 children with newly diagnosed ALL were tested by the Fluorometric Microculture Cytotoxicity Assay to measure their resistance to each of ten standard cytotoxic drugs. In the high-risk group, increased in vitro resistance to each of the drugs dexamethasone, etoposide and doxorubicin was associated with a worse clinical outcome. Combining the results for these drugs yielded a drug resistance score, showing a relative risk of relapse in the most resistant group that was 9.8 times higher than in the most sensitive group. In the standard-risk and intermediate-risk groups, final evaluation must await longer follow-up.

The new cytotoxic agent CHS 828 was equally active in vitro in samples from children with acute myeloblastic leukemia (AML) and ALL, with 50% cell kill at concentrations achievable in vivo. In AML samples CHS 828 also displayed high frequencies of synergistic interactions with four standard drugs. The well-known differences in clinical outcome between Down´s syndrome (DS) and non-DS children with acute leukemia may partly be explained by our finding of differences in drug resistance at the cellular level.

Pharmacokinetic studies were performed at the start of induction treatment of ALL. Doxorubicin was assayed by reversed-phase liquid chromatography with fluorometric detection, and vincristine by high performance liquid chromatography with electrochemical detection. Plasma doxorubicin concentrations were measured in 107 children after 23 h of a 24-h infusion. The median steady-state concentration in children 4-6 years old, a group known to have a favorable outcome of treatment, was about 50% higher than in those 1-2 and >6 years old Vincristine pharmacokinetics was evaluated in 98 children. There was no correlation between age and total body clearance or any other pharmacokinetic parameters.

In vitro testing of cellular drug resistance might be useful in predicting the outcome in high-risk ALL. The further exploration of CHS 828 in childhood leukemia seems warranted. There is no pharmacokinetic rationale for the common practice of administering relatively lower doses of vincristine to adolescents than to younger children.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2002. 85 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1189
Keyword
Obstetrics and gynaecology, cytotoxicity, drug resistance, pharmacokinetics, Acute lymphoblastic leukemia, childhood, in vitro assay, vincristine, doxorubicin, Down`s syndrome, CHS 828., Obstetrik och kvinnosjukdomar
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Pediatrics
Identifiers
urn:nbn:se:uu:diva-2664 (URN)91-554-5417-8 (ISBN)
Public defence
2002-11-01, Rosén salen, Uppsala, 09:15
Opponent
Available from: 2002-10-10 Created: 2002-10-10Bibliographically approved

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