Development and validation of a test dose strategy for once-daily i.v. busulfan: importance of fixed infusion rate dosing.

Abstract

Intravenous (i.v.) busulfan (Bu) administered once daily in myeloablative transplant regimens is convenient, effective, and relatively well tolerated. Therapeutic drug monitoring is recommended as nonrelapse mortality increases when daily exposure, as determined by the area under the plasma concentration versus time curve (AUC), exceeds 6000 μM·min. We describe sequential studies to achieve accurate prediction of treatment doses of Bu based on the kinetics of a smaller test dose. A total of 335 patients with hematologic malignancies were given daily i.v. Bu 3.2 mg/kg × 4 and fludarabine 50 mg/m(2) × 5. Pharmacokinetic monitoring was conducted for both the test dose and first treatment dose of Bu (day -5). Three different test dose schedules were evaluated: 12 mg Bu administered over 20 minutes, 0.8 mg/kg over 3 hours, and 0.8 mg/kg infused at 80 mg/h. The 3.2 mg/kg treatment doses were infused over a fixed time of 3 hours for the first 2 test dose trials and at a fixed rate of 80 mg/h for the final protocol. All test dose infusions were on day -7. In the first 2 schedules, Bu administered over a fixed time had significantly higher clearance for the test dose compared with the treatment dose. However, when both the test and the treatment doses were administered at the same infusion rate, clearance of the drug between the 2 dosing days was equivalent. Predicted day -5 AUC (AUC(-5)) showed a high linear correlation (r(2) = 0.74) to the actual AUC(-5). The error of these predictions was <20% in 98% of patients and <10% in 80%. In 24 individuals, the test dose predicted an AUC >5500 μM·min; therefore, the first Bu treatment dose was reduced to a desired target AUC. All adjusted doses fell within 20% of the targeted exposure. We conclude that a test dose strategy for therapeutic drug monitoring of daily i.v. Bu is accurate if the test and treatment doses are infused at the same rate. This approach allows targeting of therapeutic doses of Bu to desired levels and the potential for improved safety and efficacy.

• Authors: S Bill Kangarloo, Farrukh Naveed, Ella S M Ng, M Ahsan Chaudhry, Judy Wu, Nizar J Bahlis, Christopher B Brown, Andrew Daly, Peter Duggan, Michelle Geddes, Diana Quinlan, Mary Lynn Savoie, Mona Shafey, Douglas A Stewart, Jan Storek, Maggie Yang, Nancy Zacarias, Ping Yue, Anthony M Magliocco, James A Russell
• Journal: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation (Biol Blood Marrow Transplant) Vol. 18 Issue 2 Pg. 295-301 (Feb 2012) ISSN: 1523-6536 [Electronic] United States
• PMID: 21801704 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Myeloablative Agonists
• Busulfan

Topics

• Adolescent
• Adult
• Aged
• Busulfan (administration & dosage, adverse effects, pharmacokinetics)
• Female
• Hematologic Neoplasms (therapy)
• Hematopoietic Stem Cell Transplantation (methods)
• Humans
• Male
• Middle Aged
• Monitoring, Physiologic
• Myeloablative Agonists (administration & dosage, adverse effects, pharmacokinetics)
• Time Factors
• Transplantation Conditioning (methods)
• Transplantation, Homologous