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

Jessica M. Davis, Anastasia Ivanova, Yunro Chung, J. Ryan Shaw, Kamakshi V. Rao, Jonathan R. Ptachcinski, Andrew A. Sharf, Jonathan S. Serody, Paul M. Armistead, William A. Wood, James M. Coghill, Katarzyna J. Jamieson, Benjamin G. Vincent, Marcie L. Riches, Thomas C. Shea, Maurice D. Alexander

Research output: Contribution to journalArticle

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 (AUCpred) achieved with weight-based dosing, with a target AUC of 4800 µM*minute (AUCtarget). 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 (AUCfirst). 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 AUCpred from the weight-based test doses (2700.8 to 9631 µM*minute; SD, 1211.6 µM*minute) to 1.8-fold in AUCfirst 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 AUCfirst being within the ±10% target range (P =.04 for both associations). There was no significant association between AUCfirst 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.

Original languageEnglish (US)
Pages (from-to)391-397
Number of pages7
JournalBiology of Blood and Marrow Transplantation
Volume25
Issue number2
DOIs
StatePublished - Feb 2019

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Busulfan
Hematopoietic Stem Cell Transplantation
Area Under Curve
Pharmacokinetics
Weights and Measures
Body Surface Area
Recurrence
Drug Therapy

Keywords

  • Busulfan
  • Hematopoietic stem cell transplantation
  • Pharmacokinetics

ASJC Scopus subject areas

  • Hematology
  • Transplantation

Cite this

Evaluation of a Test Dose Strategy for Pharmacokinetically-Guided Busulfan Dosing for Hematopoietic Stem Cell Transplantation. / Davis, Jessica M.; Ivanova, Anastasia; Chung, Yunro; Shaw, J. Ryan; Rao, Kamakshi V.; Ptachcinski, Jonathan R.; Sharf, Andrew A.; Serody, Jonathan S.; Armistead, Paul M.; Wood, William A.; Coghill, James M.; Jamieson, Katarzyna J.; Vincent, Benjamin G.; Riches, Marcie L.; Shea, Thomas C.; Alexander, Maurice D.

In: Biology of Blood and Marrow Transplantation, Vol. 25, No. 2, 02.2019, p. 391-397.

Research output: Contribution to journalArticle

Davis, JM, Ivanova, A, Chung, Y, Shaw, JR, Rao, KV, Ptachcinski, JR, Sharf, AA, Serody, JS, Armistead, PM, Wood, WA, Coghill, JM, Jamieson, KJ, Vincent, BG, Riches, ML, Shea, TC & Alexander, MD 2019, 'Evaluation of a Test Dose Strategy for Pharmacokinetically-Guided Busulfan Dosing for Hematopoietic Stem Cell Transplantation', Biology of Blood and Marrow Transplantation, vol. 25, no. 2, pp. 391-397. https://doi.org/10.1016/j.bbmt.2018.09.017
Davis, Jessica M. ; Ivanova, Anastasia ; Chung, Yunro ; Shaw, J. Ryan ; Rao, Kamakshi V. ; Ptachcinski, Jonathan R. ; Sharf, Andrew A. ; Serody, Jonathan S. ; Armistead, Paul M. ; Wood, William A. ; Coghill, James M. ; Jamieson, Katarzyna J. ; Vincent, Benjamin G. ; Riches, Marcie L. ; Shea, Thomas C. ; Alexander, Maurice D. / Evaluation of a Test Dose Strategy for Pharmacokinetically-Guided Busulfan Dosing for Hematopoietic Stem Cell Transplantation. In: Biology of Blood and Marrow Transplantation. 2019 ; Vol. 25, No. 2. pp. 391-397.
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N2 - 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 (AUCpred) achieved with weight-based dosing, with a target AUC of 4800 µM*minute (AUCtarget). 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 (AUCfirst). 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 AUCpred from the weight-based test doses (2700.8 to 9631 µM*minute; SD, 1211.6 µM*minute) to 1.8-fold in AUCfirst 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 AUCfirst being within the ±10% target range (P =.04 for both associations). There was no significant association between AUCfirst 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.

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