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    Impact of dose and duration of therapy on dexamethasone pharmacokinetics in childhood acute lymphoblastic leukaemia-a report from the UKALL 2011 trial

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    Authors
    Jackson, RK
    Liebich, M
    Berry, P
    Errington, J
    Liu, Jizhong
    Parker, Catriona
    Moppett, J
    Samarasinghe, S
    Hough, R
    Rowntree, C
    Goulden, NJ
    Vora, A
    Kearns, PR
    Saha, Vaskar
    Hempel, G
    Irving, JAE
    Veal, GJ
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    Affiliation
    Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK
    Issue Date
    2019
    
    Metadata
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    Abstract
    INTRODUCTION: The use of dexamethasone in acute lymphoblastic leukaemia therapy contributes to short- and long-term toxicities. The UKALL 2011 randomised trial investigated whether a more intense dexamethasone dose (10 mg/m2/d x 14d, short vs 6 mg/m2/d x 28d, standard) would lead to a more rapid cytoreduction and reduced adverse effects associated with longer durations of steroids in induction. The impact of dose and duration on dexamethasone pharmacokinetics was investigated. METHODS: Blood samples were obtained on one of the first three and last three days of induction dexamethasone dosing at time points up to 8 h after oral administration. Plasma dexamethasone levels were quantified in 1084 plasma samples obtained from 174 children and a population pharmacokinetic model developed. RESULTS: Drug exposure varied significantly between patients, with a >12-fold variation in AUC0-12h values and a marked overlap in dexamethasone exposures between dose levels. Intuitively, AUC0-12h was significantly higher with short dosing (10 mg/m2/d), but cumulative exposure was significantly higher with standard dosing over 28 days, after a higher cumulative dose. Concomitant rasburicase administration was associated with a 60% higher dexamethasone clearance. Day 8 bone marrow response was comparable between dosing arms, but those with <5% blast count exhibited a greater mean dexamethasone exposure than those with >5%. No statistical differences were observed between arms in terms of steroid-related toxicity or minimal residual disease at the end of induction. CONCLUSION: The potential significance of dexamethasone AUC0-12h on early response and higher cumulative exposure on the standard arm suggest that duration of therapy and exposure may be more important factors than absolute dose from a clinical pharmacology perspective.
    Citation
    Jackson RK, Liebich M, Berry P, Errington J, Liu J, Parker C, et al. Impact of dose and duration of therapy on dexamethasone pharmacokinetics in childhood acute lymphoblastic leukaemia-a report from the UKALL 2011 trial. Eur J Cancer. 2019 Oct;120:75-85.
    Journal
    European Journal of Cancer
    URI
    http://hdl.handle.net/10541/622222
    DOI
    10.1016/j.ejca.2019.07.026
    PubMed ID
    31499383
    Additional Links
    https://dx.doi.org/10.1016/j.ejca.2019.07.026
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.ejca.2019.07.026
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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