Asparaginase May Influence Dexamethasone Pharmacokinetics in Acute Lymphoblastic Leukemia

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.