Impact of dose and duration of therapy on dexamethasone pharmacokinetics in childhood acute lymphoblastic leukaemia-a report from the UKALL 2011 trial
dc.contributor.author | Jackson, RK | |
dc.contributor.author | Liebich, M | |
dc.contributor.author | Berry, P | |
dc.contributor.author | Errington, J | |
dc.contributor.author | Liu, Jizhong | |
dc.contributor.author | Parker, Catriona | |
dc.contributor.author | Moppett, J | |
dc.contributor.author | Samarasinghe, S | |
dc.contributor.author | Hough, R | |
dc.contributor.author | Rowntree, C | |
dc.contributor.author | Goulden, NJ | |
dc.contributor.author | Vora, A | |
dc.contributor.author | Kearns, PR | |
dc.contributor.author | Saha, Vaskar | |
dc.contributor.author | Hempel, G | |
dc.contributor.author | Irving, JAE | |
dc.contributor.author | Veal, GJ | |
dc.date.accessioned | 2019-10-07T15:16:45Z | |
dc.date.available | 2019-10-07T15:16:45Z | |
dc.date.issued | 2019 | en |
dc.identifier.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. | en |
dc.identifier.pmid | 31499383 | en |
dc.identifier.doi | 10.1016/j.ejca.2019.07.026 | en |
dc.identifier.uri | http://hdl.handle.net/10541/622222 | |
dc.description.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. | en |
dc.language.iso | en | en |
dc.relation.url | https://dx.doi.org/10.1016/j.ejca.2019.07.026 | en |
dc.title | Impact of dose and duration of therapy on dexamethasone pharmacokinetics in childhood acute lymphoblastic leukaemia-a report from the UKALL 2011 trial | en |
dc.type | Article | en |
dc.contributor.department | Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK | en |
dc.identifier.journal | European Journal of Cancer | en |
dc.description.note | en] |