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J Clin Oncol. 2008 Apr 20;26(12):1932-9. doi: 10.1200/JCO.2007.13.8404.

Asparaginase may influence dexamethasone pharmacokinetics in acute lymphoblastic leukemia.

Author information

1
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794, USA.

Abstract

PURPOSE:

Dexamethasone is used widely in oncology, but pharmacokinetic studies are lacking. We evaluated dexamethasone pharmacokinetics in children with acute lymphoblastic leukemia.

PATIENTS AND METHODS:

We assessed 214 children with acute lymphoblastic leukemia who received 418 courses of oral dexamethasone (8 mg/m(2)/d) on days 1 and 8 of reinduction. Extensive asparaginase use preceded reinduction in the 101 children in the standard/high-risk treatment arm but not in the 113 children in the low-risk treatment arm. A one-compartment model with first-order absorption and disposition was fit to dexamethasone plasma concentrations by using maximum a posteriori probability estimation; we evaluated covariates by using linear mixed models.

RESULTS:

Interpatient and intrapatient variabilities in apparent clearance were substantial; they were 46% and 53%, respectively. Variability was explained by the serum albumin concentration (P < .0001), concomitant use of fentanyl (P = .008) and ketoconazole (P = .03), and age (P = .006). Apparent clearance was higher in the low-risk arm (P < .001) and was related to a greater serum albumin concentration (P < .001) and to a lower exposure to asparaginase than in the standard/high-risk arm. Hypoalbuminemia, a biomarker of asparaginase activity, was associated with a lower dexamethasone apparent clearance (P = .04) in patients in the standard/high-risk arm that was more pronounced in those not allergic to asparaginase. Ethnicity or gender did not explain apparent clearance variability.

CONCLUSION:

Dexamethasone pharmacokinetics are highly variable and are related to the concurrent use of particular drugs, age, and treatment intensity. Patients allergic to asparaginase may be doubly disadvantaged: they not only suffer from diminished exposure to asparaginase but also, by maintaining high clearance of dexamethasone, may experience fewer antileukemic effects of dexamethasone.

Comment in

PMID:
18421047
DOI:
10.1200/JCO.2007.13.8404
[Indexed for MEDLINE]

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