|Values are valid only on day of printing.|
Guiding dosage adjustments to achieve complete bone marrow ablation while minimizing dose-dependent toxicity
Busulfan is an alkylating agent used to ablate bone marrow cells prior to hematopoietic stem cell transplantation for chronic myelogenous leukemia.(1) Busulfan is typically administered intravenously (IV) at the recommended dosage of 0.8 mg/kg of actual or ideal body weight (whichever is lower) and given once every 6 hours over 4 days for a total of 16 doses. Dose-limiting toxicity of busulfan includes veno-occlusive liver disease, seizures, and coma. To avoid toxicity while ensuring busulfan dose adequacy to completely ablate the bone marrow, IV dosing should be guided by pharmacokinetic (PK) evaluation of area under the curve (AUC) and clearance after the first dose.(2) The PK evaluation should be carried out at the end of the first dose, with results of PK testing available to facilitate dose adjustment before beginning the fifth dose.
AREA UNDER THE CURVE
This test should only be ordered when the following criteria are met:
-Busulfan dosing protocol must be intravenous (IV) administration of 8 mg/kg doses every 6 hours over 4 days, for a total of 16 doses
-Specimens must be drawn as described below:
- 1 specimen drawn immediately after termination of a 2-hour IV infusion of busulfan
- 1 specimen drawn 1 hour after the infusion is terminated
- 1 specimen drawn 2 hours after the infusion is terminated
- 1 specimen drawn 4 hours after the infusion is terminated
These results will be used to calculate a 6-hour area under the curve (AUC). If a different dosing or specimen collection protocol is used, or if different calculations are required, please contact the Laboratory Director.
The optimal result for AUC (6 hour) derived from this pharmacokinetic (PK) evaluation of IV busulfan is 1,100 (mcmol/L)(min).
AUC results >1,500 (mcmol/L)(min) are associated with hepatic veno-occlusive disease. A dose reduction should be considered before the next busulfan infusion.
AUC results <900 (mcmol/L)(min) are consistent with incomplete bone marrow ablation. A dose increase should be considered before the next busulfan infusion.
Clearance of busulfan in patients with normal renal function is usually in the range of 2.1 to 3.5 (mL/min)/kg.
Elevated AUC is typically associated with clearance <2.5 (mL/min)/kg, most frequently due to diminished activity of glutathione S-transferase A1-1 activity.(3)
This assay requires 4 plasma specimens. Each specimen must be drawn at the intervals described above and labeled with the exact draw time. The specimen accession times should reflect these times. The time the drug administration is started and terminated, the patient's dose (mg every 6 hours), body weight (kg), and age (years) must be submitted with the specimens. Without infusion start time, exact time of specimen draw, dose, and body weight, the area under the curve and clearance cannot be calculated. Age is required for assessment of the correct dose per body weight.
1. Santos GW, Tutschka PJ, Brookmeyer R, et al: Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med 1983 December 1;309(22):1347-1353
2. Slattery JT, Sanders JE, Buckner CD, et al: Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics. Bone Marrow Transpl 1995 July;16(1):31-42
3. Slattery JT, Risler LJ: Therapeutic monitoring of busulfan in hematopoietic stem cell transplantation. Ther Drug Monit 1998 October;20(5):543-549
4. Czerwinski M, Gibbs M, Slattery JT: Busulfan conjugation by glutathione S-transferases alpha, mu, and pi. Drug Metab Dispos 1996 September;24(9):1015-1019