Evaluation of the Pharmacokinetics and Efficacy of a Busulfan Test Dose in Adult Patients Undergoing Myeloablative Hematopoietic Cell Transplantation

Abstract

Owing to interpatient variability in busulfan exposure, therapeutic monitoring of busulfan is often used in myeloablative allogeneic transplantation to ensure that patients are near the optimal steady-state goal of 900 ng/mL. One challenge in therapeutic monitoring of busulfan is the brief course of busulfan treatment, requiring prompt analysis and dose adjustments as needed. Pharmacokinetic evaluation of a busulfan test dose before the start of the conditioning regimen would allow for all conditioning regimen doses to be given at the calculated optimized dose. An observational study was completed to evaluate the effects of a busulfan test dose of 0.9 mg/kg administered before the start of a myeloablative intravenous busulfan-based conditioning regimen. Sixty adult patients who received a busulfan conditioning regimen were reviewed, including 30 patients prior to the implementation of the busulfan test dose (pretest dose group) and 30 patients who received the busulfan test dose (posttest dose group). The primary objective was a pharmacokinetic evaluation of the percentage of patients who achieved the desired steady-state goal using the test dose strategy. The safety and efficacy of the busulfan test dose were evaluated as well. The average busulfan steady-state level after the first dose of the conditioning regimen was significantly lower in the pre-test dose group compared with the post-test dose group (660 ng/mL versus 879.9 ng/mL; P < 0.001). Compared with the post-test dose group, significantly fewer patients in the pre-test dose group were within 10% of the busulfan steady-state goal (10% versus 73.3%; P < 0.001) or within 5% of the goal (0% versus 53%; P < 0.001). Requirements for parenteral nutrition and/or patient-controlled analgesia owing to mucositis and rates of veno-occlusive disease were not significantly different between the pre-test dose group and the post-test dose group. The rates of disease relapse, mortality, and acute graft-versus-host disease were similar in the two groups. A pretransplantation busulfan test dose of 0.9 mg/kg improved the patients' ability to reach therapeutic busulfan target levels after the first conditioning dose and resulted in fewer adjustments during conditioning. The use of a busulfan test dose did not significantly increase patients' risk of mucositis or other safety outcomes.

Risk Score for the Development of Veno-Occlusive Disease after Allogeneic Hematopoietic Cell Transplant

“…And while use of PK monitoring may result in improved overall outcomes in patients undergoing allogeneic HCT, it is possible that important associations between PK monitoring and relatively infrequent outcomes, such as VOD, may not have been identified in prior studies with less statistical power. One hypothesized mechanism to explain this association is that use of PK monitoring may generally result in higher exposure to busulfan, as reported by Weil et al using data from a single institution 23 . In their adult population, the patients’ busulfan doses were increased in 96.7% of cases after the first dose level, which suggests that patients treated without PK monitoring generally are exposed to a lower level of busulfan.…”

Test Dose Pharmacokinetics in Pediatric Patients Receiving Once‐Daily IV Busulfan Conditioning for Hematopoietic Stem Cell Transplant: A Reliable Approach?

“…However, changes in clearance within patients varied widely between test and full‐dose conditions. This is in contrast to adult populations in whom the test‐dose strategy has been applied and shown to improve attainment of busulfan target exposures . Mean (range) clearance in adults is ∼2.5 mL/[min·kg] (∼1.5‐4.3 mL/[min·kg]), with low intrasubject variabilities reported .…”

“…This is in contrast to adult populations in whom the test-dose strategy has been applied and shown to improve attainment of busulfan target exposures. [6][7][8][9] Mean (range) clearance in adults is ß2.5 mL/[min·kg] (ß1.5-4.3 mL/[min·kg]), with low intrasubject variabilities reported. 2 The exact underlying reasons for the discrepancies observed in these pediatric patients in comparison to adult populations are unclear but may be attributable to a number of factors.…”

“…Another method has been to perform a test dose before the full conditioning regimen, which involves the administration of IV busulfan at a dose of ∼0.8 mg/kg to assess the patient's pharmacokinetics (PK), with full once‐daily doses adjusted to target exposures assuming dose linearity. This approach has been shown to accurately predict once‐daily dosing requirements and improve outcomes in adult HSCT patients . However, data on the reliability of this approach in children are limited.…”

“…This approach has been shown to accurately predict once-daily dosing requirements and improve outcomes in adult HSCT patients. [6][7][8][9] However, data on the reliability of this approach in children are limited. Available studies in pediatric populations reached target levels in 60% to 84% of cases where both test and full doses were examined.…”