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Pharmacokinetics and Pharmacodynamics of Oral Etoposide in Children With Relapsed or Refractory Acute Lymphoblastic Leukemia

Mathew J. Edick, Amar Gajjar, Hazem H. Mahmoud, Matthijs E.C. van de Poll, Patricia L. Harrison, John C. Panetta, Gaston K. Rivera, Raul C. Ribeiro, John T. Sandlund, James M. Boyett, Ching-Hon Pui, Mary V. Relling

From the Departments of Pharmaceutical Sciences, Hematology/Oncology, and Biostatistics, St. Jude Children’s Research Hospital, and Colleges of Pharmacy and Medicine, The University of Tennessee, Memphis, TN; and College of Medicine, University of Missouri, Columbia, MO.

Address reprint requests to Mary V. Relling, PharmD, Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38105; email: mary.relling{at}stjude.org.

Purpose: To study the pharmacokinetics and pharmacodynamics of once- versus twice-daily oral etoposide in children with relapsed or refractory acute lymphoblastic leukemia (ALL).

Patients and Methods: Fifty-eight patients were randomly assigned to etoposide at 50 mg/m²/d with once- versus twice-daily doses for 22 days. On day 8, vincristine, asparaginase, and dexamethasone were started. Etoposide pharmacokinetics and pharmacodynamics were studied for 47, 28, and 26 patients on day 1, 8, and 22, respectively, of remission reinduction therapy.

Results: Of 48 patients with pharmacokinetic data, 42 (87.5%) achieved complete remission, three (6.3%) failed to achieve remission, and three (6.3%) died during induction. Median etoposide day 8 area under concentration-time curve (AUC) and cumulative AUC tended to be greater (P = .06 and P = .07, respectively) in patients (n = 23) who achieved complete remission (24 and 522 µmol/L • h, respectively) than in patients (n = 3) who did not (14 and 303 µmol/L • h, respectively). Three of eight patients with plasma concentrations exceeding 1.7 µM (1 µg/mL) for more than 8 hours daily, compared with one of 20 patients with concentrations exceeding 1.7 µM for 8 hours daily, were unable to receive all 22 days of etoposide because of toxicity. There was no difference in the AUC at day 1 or day 8 with once- versus twice-daily doses (P = .55 and P = .86, respectively).

Conclusion: A pharmacodynamic relationship exists between systemic etoposide exposure and response to therapy when oral etoposide is used as part of remission induction regimens for relapsed or refractory childhood ALL.

Ching-Hon Pui is the American Cancer Society F.M. Kirby Clinical Research Professor.

Supported by grants CA21765, CA51001, and CA23944 from the National Institutes of Health, Department of Health and Human Services, Bethesda, MD; by a Center of Excellence grant from the state of Tennessee; and by American Lebanese Syrian Associated Charities (ALSAC).

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