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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.
Eur J Cancer 2019; 120:75-85EJ

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.

Authors+Show Affiliations

Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Münster, Germany.Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, UK.Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, UK.Department of Paediatric Haematology and Oncology, Bristol Royal Hospital for Children, UK.Department of Haematology, Great Ormond Street Hospital for Children, London, UK.University College Hospital, London, UK.University Hospital of Wales, Cardiff, UK.Department of Haematology, Great Ormond Street Hospital for Children, London, UK.Department of Paediatric Haematology, Great Ormond Street Hospital, UK.Cancer Research UK Clinical Trials Unit, National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Cancer and Genomic Studies, University of Birmingham, UK.Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, UK; Tata Translational Cancer Research Centre, Tata Medical Center, Kolkata, India.Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Münster, Germany.Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK. Electronic address: G.J.Veal@ncl.ac.uk.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31499383

Citation

Jackson, Rosanna K., et al. "Impact of Dose and Duration of Therapy On Dexamethasone Pharmacokinetics in Childhood Acute Lymphoblastic Leukaemia-a Report From the UKALL 2011 Trial." European Journal of Cancer (Oxford, England : 1990), vol. 120, 2019, pp. 75-85.
Jackson RK, Liebich M, Berry P, 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;120:75-85.
Jackson, R. K., Liebich, M., Berry, P., Errington, J., Liu, J., Parker, C., ... Veal, G. J. (2019). Impact of dose and duration of therapy on dexamethasone pharmacokinetics in childhood acute lymphoblastic leukaemia-a report from the UKALL 2011 trial. European Journal of Cancer (Oxford, England : 1990), 120, pp. 75-85. doi:10.1016/j.ejca.2019.07.026.
Jackson RK, 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;120:75-85. PubMed PMID: 31499383.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Impact of dose and duration of therapy on dexamethasone pharmacokinetics in childhood acute lymphoblastic leukaemia-a report from the UKALL 2011 trial. AU - Jackson,Rosanna K, AU - Liebich,Martina, AU - Berry,Philip, AU - Errington,Julie, AU - Liu,Jizhong, AU - Parker,Catriona, AU - Moppett,John, AU - Samarasinghe,Sujith, AU - Hough,Rachael, AU - Rowntree,Clare, AU - Goulden,Nick J, AU - Vora,Ajay, AU - Kearns,Pamela R, AU - Saha,Vaskar, AU - Hempel,Georg, AU - Irving,Julie A E, AU - Veal,Gareth J, Y1 - 2019/09/06/ PY - 2019/05/03/received PY - 2019/07/01/revised PY - 2019/07/23/accepted PY - 2019/9/10/pubmed PY - 2019/9/10/medline PY - 2019/9/10/entrez KW - Acute lymphoblastic leukaemia KW - Dexamethasone KW - Paediatrics KW - Pharmacokinetics SP - 75 EP - 85 JF - European journal of cancer (Oxford, England : 1990) JO - Eur. J. Cancer VL - 120 N2 - 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. SN - 1879-0852 UR - https://www.unboundmedicine.com/medline/citation/31499383/Impact_of_dose_and_duration_of_therapy_on_dexamethasone_pharmacokinetics_in_childhood_acute_lymphoblastic_leukaemia-a_report_from_the_UKALL_2011_trial DB - PRIME DP - Unbound Medicine ER -