Mechanisms of dexamethasone-induced disturbed sleep and fatigue in paediatric patients receiving treatment for ALL
Background: Dexamethasone contributes to high cure rates in paediatric acute lymphoblastic leukaemia (ALL) but significantly and adversely alters sleep and fatigue. Herein we explored three mechanisms (pharmacokinetics, serum albumin and pharmacogenetics) through which dexamethasone may cause debilitating fatigue and disrupted sleep. Methods: We enrolled 100 patients on a 10-d study: 5-d of no dexamethasone (OFF DEX) followed by 5-d of dexamethasone (ON DEX) during continuation chemotherapy. Sleep variables were collected with continuous actigraphy on days 1 through 5, both OFF DEX and ON DEX. On days 2 and 5 of each 5-d period, parents and patients 7 years of age and older completed a sleep diary and Fatigue Scale questionnaire. Blood was collected at 0 (pre-dexamethasone), 1, 2, 4 and 8 h after the first oral dexamethasone dose for pharmacokinetic analysis. Serum albumin concentration was retrospectively analysed in stored samples. Patient DNA was genotyped for 99 polymorphic loci in candidate genes associated with glucocorticoid metabolism. Results: Dexamethasone clearance was significantly greater in younger patients than in older ones and in lower risk patients. In multiple regression models, risk group was significantly related to pharmacokinetic parameters. We found that polymorphisms in three genes (AHSG, IL6, POLDIP3) were significantly associated with sleep measures but not with fatigue. Conclusion: Risk group had the most significant relationship with disrupted sleep in patients while on dexamethasone. Serum albumin levels had neither a direct relationship with sleep or fatigue variables nor an indirect relationship through systemic exposure to dexamethasone. We identified candidate genes that may help explain the adverse events of disrupted sleep in paediatric patients receiving dexamethasone. © 2010 Elsevier Ltd. All rights reserved.
Vallance, K; Liu, W; Mandrell, BN; Panetta, JC; Gattuso, JS; Hockenberry, M; Zupanec, S; Yang, L; Yang, J; Hinds, PS
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