Evaluation of a Test Dose Strategy for Pharmacokinetically-Guided Busulfan Dosing for Hematopoietic Stem Cell Transplantation

Abstract

Targeted busulfan dosing helps limit chemotherapy-related toxicity and optimize disease outcomes in hematopoietic stem cell transplantation (HCT). The objective of this study was to evaluate busulfan exposure from a pharmacokinetic (PK)-guided dosing strategy using a test dose. This retrospective evaluation included adult patients who underwent HCT at our institution with busulfan-based myeloablative (>9 mg/kg) conditioning between January 2014 and October 2015. A weight-based test dose of 0.8 mg/kg was used with PK assessments to predict area under the curve (AUC) achieved with weight-based dosing, with a target AUC of 4800 µM*minute (AUC). PK from the test dose was then used to calculate a PK-guided first myeloablative busulfan dose. PK assessments were also done after the first dose to assess if the goal area under the curve (AUC) had been achieved (AUC). A PK-guided first dose resulted in achievement of target AUC with target ranges of ±10% in 50% of patients, ±15% in 75%, and ±20% in 94%. This was an improved rate of target achievement compared with the 33%, 44%, and 63% of patients who achieved the desired AUC for these respective target ranges when using weight-based dosing (P = .12, .004, and <.001, respectively). The PK-guided strategy also decreased the variability of AUC from 3.6-fold in AUC from the weight-based test doses (2700.8 to 9631 µM*minute; SD, 1211.6 µM*minute) to 1.8-fold in AUC from the PK-guided first doses (3672.1 to 6609.8 µM*minute; SD, 574.7 µM*minute). This reflects a 2-fold improvement in AUC variability with a PK-guided dosing strategy. This is also improved from the 3-fold variability in AUC reported in other studies. Weight and body surface area were significantly associated with the likelihood of AUC being within the ±10% target range (P = .04 for both associations). There was no significant association between AUC and death, relapse, or a composite of the two. These results demonstrate a significant improvement in target AUC attainment and less interpatient variability with PK-guided dosing using a test dose strategy compared with weight-based dosing.

Utilization of a Population Pharmacokinetic Model to Improve a Busulfan Test‐Dose Strategy in Allogeneic Hematopoietic Cell Transplant Recipients

“…[12][13][14][15] The use of a test-dose strategy for PK-guided busulfan dosing has been previously evaluated and shown to improve the number of patients achieving target busulfan exposures. 15,[19][20][21][22]24 Using NCA, Davis et al 19 showed that 33%, 46%, and 63% of patients receiving conventional weight-based dosing were estimated to have achieved an AUC within the target ranges of 4800 μM*min ±10%, ±15%, and ±20%, respectively. 19 Following a PK-guided test-dose procedure, 50%, 75%, and 94% of patient AUCs were within the AUC target ±10%, ±15%, and ±20% ranges, respectively.…”

“…15,[19][20][21][22]24 Using NCA, Davis et al 19 showed that 33%, 46%, and 63% of patients receiving conventional weight-based dosing were estimated to have achieved an AUC within the target ranges of 4800 μM*min ±10%, ±15%, and ±20%, respectively. 19 Following a PK-guided test-dose procedure, 50%, 75%, and 94% of patient AUCs were within the AUC target ±10%, ±15%, and ±20% ranges, respectively. In our study, the proportion of patient AUCs, estimated using NCA, within these ranges are consistent with the results reported by Davis et al However, we demonstrate that busulfan PK among adult allo-HCT recipients receiving MAC dosing can be reasonably described by a popPK model.…”

“…Achieving busulfan plasma exposure within a therapeutic window of approximately 4000–6000 μM*min has been shown to improve OS and reduce toxicity in allo‐HCT recipients 12–15 . The use of a test‐dose strategy for PK‐guided busulfan dosing has been previously evaluated and shown to improve the number of patients achieving target busulfan exposures 15,19–22,24 . Using NCA, Davis et al 19 showed that 33%, 46%, and 63% of patients receiving conventional weight‐based dosing were estimated to have achieved an AUC within the target ranges of 4800 μM*min ±10%, ±15%, and ±20%, respectively 19 .…”

“…5 The busulfan test-dose strategy has been shown to increase the number of patients achieving exposure goals and improve therapeutic outcomes. [19][20][21][22] At the University of North Carolina Chapel Hill Medical Center (UNCMC), an intravenous busulfan test-dose of 0.8 mg/kg is initially administered to adult allo-HCT recipients. Following test-dose administration, serial pharmacokinetic (PK) samples obtained at prespecified time points are used to calculate and estimate individual PK parameters (eg, AUC and clearance) using noncompartmental analysis (NCA) methods.…”

External Evaluation of Population Pharmacokinetic Models of Busulfan in Chinese Adult Hematopoietic Stem Cell Transplantation Recipients

“…First is the conventional PK-guided dose adjustment routinely performed in the clinical practice. AUC or Css can be calculated either by multiple pharmacokinetic samples (at least five samples) or a reliable limited sampling strategy (LSS) ( Malär et al, 2011 ; Davis et al, 2019 ). Dosage can be adjusted by comparing the current AUC or Css with the target values.…”