Case 1055 - A Male Undergoing Therapeutic Drug Monitoring for Busulfan Dosing

Contributed by Megan Zilla, MD, PhD and Raman Venkataramanan, PhD


The patient is a male is his early 60s with a history of primary refractory AML who was admitted to the hospital for matched unrelated bone marrow transplantation. He was on prophylactic metronidazole before admission, and unbeknownst to the clinical team, he took a dose of metronidazole the evening before beginning induction with Flu/Bu4/ATG. Per protocol at our institution, therapeutic drug monitoring (TDM) of busulfan was performed by collecting blood samples at time zero and at 3, 4, 6 and 8 hours after beginning the infusion. The drug levels were measured using HPLC-MS/MS. The values obtained for all four busulfan doses on this patient are graphed in Figure 1 and presented in Table 1. The target for average busulfan area under the curve (AUC) was 4800 uMol/L*min for four doses, given every 24 hours for 4 days. With this in mind, the first dose given was 240 mg. However, when the busulfan levels were measured after the first dose, the AUC was 7372 uMol/L*min, which represents 154% of the expected level. The clearance rate was calculated to be 1.93 mL/min/kg, but is expected to be 3.0 mL/min/kg. At this point, the clinical team became aware that the patient had taken the metronidazole dose. Additionally, for the desired average AUC target of 4800 uMol/L*min, a -47% dose adjustment, for a dose of 128 mg, was recommended to begin at dose 2. TDM for the second dose showed an AUC of 3920 uMol/L*min. The clearance was 1.94 mL/min/kg, which is very similar to the first dose, indicating the effects of metronidazole were ongoing. For day 3, a dose of 128 mg was also used, and this time the AUC was 3184 uMol/L*min with a clearance of 2.39 mL/min/kg. This increased clearance rate indicated the effects of metronidazole were beginning to wear off, and a higher dose of 190 mg was recommended for the fourth dose of busulfan. TDM for the fourth dose showed an AUC of 4720 uMol/L*min and a clearance rate again of 2.39 mL/min/kg. The average AUC for the four doses was 4799 uMol/L*min, which was very close to the target. A clearance rate of 2.39 mL/min/kg, however, is still below the anticipated clearance of 3.0 mL/min/kg, suggesting that even at approximately 80 hours after metronidazole ingestion, it was still effecting the busulfan clearance.

   Table 1. TDM Results Summary



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