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Asparaginase May Influence Dexamethasone Pharmacokinetics in Acute Lymphoblastic Leukemia

Lei Yang, John C. Panetta, Xiangjun Cai, Wenjian Yang, Deqing Pei, Cheng Cheng, Nancy Kornegay, Ching-Hon Pui, Mary V. Relling

From the Departments of Pharmaceutical Sciences, Oncology, and Biostatistics, St Jude Children's Research Hospital; and the Colleges of Medicine and Pharmacy, University of Tennessee, Memphis, TN

Corresponding author: Mary V. Relling, PharmD, Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794; e-mail: mary.relling{at}stjude.org

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/m²/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.

Supported by Grants No. CA 51001 and CA 21765 from the National Institutes of Health, National Cancer Institute; by a Center of Excellence grant from the state of Tennessee; and by the American Lebanese Syrian Associated Charities. C.-H.P. is an American Cancer Society Professor.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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