Skip to main content

Prediction of intravenous busulfan clearance by endogenous plasma biomarkers using global pharmacometabolomics

Metabolomics volume 12, Article number: 161 (2016) Cite this article

Abstract

Introduction

High-dose busulfan (busulfan) is an integral part of the majority of hematopoietic cell transplantation conditioning regimens. Intravenous (IV) busulfan doses are personalized using pharmacokinetics (PK)-guided dosing where the patient’s IV busulfan clearance is calculated after the first dose and is used to personalize subsequent doses to a target plasma exposure. PK-guided dosing has improved patient outcomes and is clinically accepted but highly resource-intensive.

Objective

We sought to discover endogenous plasma biomarkers predictive of IV busulfan clearance using a global pharmacometabolomics-based approach

Methods

Using LC-QTOF, we analyzed 59 (discovery) and 88 (validation) plasma samples obtained before IV busulfan administration.

Results

In the discovery dataset, we evaluated the association of the relative abundance of 1885 ions with IV busulfan clearance and found 21 ions that were associated with IV busulfan clearance tertiles (r2 ≥ 0.3). Identified compounds were deoxycholic acid and/or chenodeoxycholic acid, and linoleic acid. We used these 21 ions to develop a parsimonious seven-ion linear predictive model that accurately predicted IV busulfan clearance in 93 % (discovery) and 78 % (validation) of samples.

Conclusion

IV busulfan clearance was significantly correlated with the relative abundance of 21 ions, seven of which were included in a predictive model that accurately predicted IV busulfan clearance in the majority of the validation samples. These results reinforce the potential of pharmacometabolomics as a critical tool in personalized medicine, with the potential to improve the personalized dosing of drugs with a narrow therapeutic index such as busulfan.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3

References

  • Abbasi, N., Vadnais, B., Knutson, J. A., Blough, D. K., Kelly, E. J., O’Donnell, P. V., et al. (2011). Pharmacogenetics of intravenous and oral busulfan in hematopoietic cell transplant recipients. Journal of Clinical Pharmacology, 51(10), 1429–1438. doi:10.1177/0091270010382915.

    CAS  PubMed  Article  Google Scholar 

  • Almog, S., Kurnik, D., Shimoni, A., Loebstein, R., Hassoun, E., Gopher, A., et al. (2011). Linearity and stability of intravenous busulfan pharmacokinetics and the role of glutathione in busulfan elimination. Biology of Blood and Marrow Transplantation, 17(1), 117–123. doi:10.1016/j.bbmt.2010.06.017.

    CAS  PubMed  Article  Google Scholar 

  • Anderson, B. J., & Holford, N. H. (2008). Mechanism-based concepts of size and maturity in pharmacokinetics. Annual Review of Pharmacology and Toxicology, 48, 303–332. doi:10.1146/annurev.pharmtox.48.113006.094708.

    CAS  PubMed  Article  Google Scholar 

  • Anderson, B. J., & Holford, N. H. (2009). Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metabolism and Pharmacokinetics, 24(1), 25–36.

    CAS  PubMed  Article  Google Scholar 

  • Benton, H. P., Want, E. J., & Ebbels, T. M. (2010). Correction of mass calibration gaps in liquid chromatography-mass spectrometry metabolomics data. Bioinformatics, 26(19), 2488–2489. doi:10.1093/bioinformatics/btq441.

    CAS  PubMed  Article  Google Scholar 

  • Buhlmann, P., Kalisch, M., & Meier, L. (2014). High-dimensional statistics with a view toward applications in biology. Annual Review of Statistics and Its Application, 1(1), 255–278. doi:10.1146/annurev-statistics-022513-115545.

    Article  Google Scholar 

  • Chaudhry, A. S., Thirumaran, R. K., Yasuda, K., Yang, X., Fan, Y., Strom, S. C., et al. (2013). Genetic variation in aldo-keto reductase 1D1 (AKR1D1) affects the expression and activity of multiple cytochrome P450s. Drug Metabolism and Disposition, 41(8), 1538–1547. doi:10.1124/dmd.113.051672.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Clayton, T. A., Lindon, J. C., Cloarec, O., Antti, H., Charuel, C., Hanton, G., et al. (2006). Pharmaco-metabonomic phenotyping and personalized drug treatment. Nature, 440(7087), 1073–1077. doi:10.1038/nature04648.

    CAS  PubMed  Article  Google Scholar 

  • Clayton, T. A., Baker, D., Lindon, J. C., Everett, J. R., & Nicholson, J. K. (2009). Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proceedings of the National Academy of Sciences United States of America, 106(34), 14728–14733. doi:10.1073/pnas.0904489106.

    CAS  Article  Google Scholar 

  • Copelan, E. A. (2006). Hematopoietic stem-cell transplantation. New England Journal of Medicine, 354(17), 1813–1826.

    CAS  PubMed  Article  Google Scholar 

  • Copelan, E. A., Hamilton, B. K., Avalos, B., Ahn, K. W., Bolwell, B. J., Zhu, X., et al. (2013). Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared to TBI. Blood. doi:10.1182/blood-2013-07-514448.

    PubMed  PubMed Central  Google Scholar 

  • Core Team, R. (2014). R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing.

    Google Scholar 

  • Cortinez, L. I., Anderson, B. J., Penna, A., Olivares, L., Munoz, H. R., Holford, N. H., et al. (2010). Influence of obesity on propofol pharmacokinetics: Derivation of a pharmacokinetic model. British Journal of Anaesthesia, 105(4), 448–456. doi:10.1093/bja/aeq195.

    CAS  PubMed  Article  Google Scholar 

  • Czerwinski, M., Gibbs, J. P., & Slattery, J. T. (1996). Busulfan conjugation by glutathione S-transferases alpha, mu, and pi. Drug Metabolism and Disposition, 24(9), 1015–1019.

    CAS  PubMed  Google Scholar 

  • Deeg, H. J., Storer, B. E., Boeckh, M., Martin, P. J., McCune, J. S., Myerson, D., et al. (2006). Reduced incidence of acute and chronic graft-versus-host disease with the addition of thymoglobulin to a targeted busulfan/cyclophosphamide regimen. Biology of Blood and Marrow Transplantation, 12(5), 573–584.

    CAS  PubMed  Article  Google Scholar 

  • Ehrsson, H., & Hassan, M. (1984). Binding of busulfan to plasma proteins and blood cells. Journal of Pharmacy and Pharmacology, 36(10), 694–696.

    CAS  PubMed  Article  Google Scholar 

  • Ehrsson, H., Hassan, M., Ehrnebo, M., & Beran, M. (1983). Busulfan kinetics. Clinical Pharmacology and Therapeutics, 34, 86–89.

    CAS  PubMed  Article  Google Scholar 

  • El-Serafi, I., Naughton, S., Saghafian, M., Abedi-Valugerdi, M., Mattsson, J., Hagbjörk, A., et al. (2014). The role of flavin-containing monooxygenase 3 (FMO3) in busulphan metabolism. Karolinska Institute, PhD Defense, 5 September 2014.

  • Everett, J. R. (2015). Pharmacometabonomics in humans: A new tool for personalized medicine. Pharmacogenomics, 16(7), 737–754. doi:10.2217/pgs.15.20.

    CAS  PubMed  Article  Google Scholar 

  • Food & Drug Administration, F. D. A. (2000). Guidance for Industry: bioavailability and bioequivalence studies for orally administered drug products—General considerations. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM154838.pdf. Accessed 18 Oct 2013.

  • Gibbs, J. P., Czerwinski, M., & Slattery, J. T. (1996). Busulfan-glutathione conjugation catalyzed by human liver cytosolic glutathione S-transferases. Cancer Research, 56(16), 3678–3681.

    CAS  PubMed  Google Scholar 

  • Gibbs, J. P., Murray, G., Risler, L., Chien, J. Y., Dev, R., & Slattery, J. T. (1997). Age-dependent tetrahydrothiophenium ion formation in young children and adults receiving high-dose busulfan. Cancer Research, 57(24), 5509–5516.

    CAS  PubMed  Google Scholar 

  • Hassan, M., & Ehrsson, H. (1987). Metabolism of 14C-busulfan in isolated perfused rat liver. European Journal of Drug Metabolism and Pharmacokinetics, 12(1), 71–76.

    CAS  PubMed  Article  Google Scholar 

  • Hassan, M., Oberg, G., Ehrsson, H., Ehrnebo, M., Wallin, I., Smedmyr, B., et al. (1989). Pharmacokinetic and metabolic studies of high-dose busulphan in adults. European Journal of Clinical Pharmacology, 36(5), 525–530.

    CAS  PubMed  Article  Google Scholar 

  • Hassan, M., Fasth, A., Gerritsen, B., Haraldsson, A., Syruckova, Z., van den Berg, H., et al. (1996). Busulphan kinetics and limited sampling model in children with leukemia and inherited disorders. Bone Marrow Transplantation, 18(5), 843–850.

    CAS  PubMed  Google Scholar 

  • Huang, L., Scheipl, F., Goldsmith, J., Gellar, J., Harezlak, J., McLean, M. W., et al. (2015). refund: Regresson with Functional Data. (R package version 0.1–12. ed.).

  • Janmahasatian, S., Duffull, S. B., Ash, S., Ward, L. C., Byrne, N. M., & Green, B. (2005). Quantification of lean bodyweight. Clinical Pharmacokinetics, 44(10), 1051–1065.

    PubMed  Article  Google Scholar 

  • Janmahasatian, S., Duffull, S. B., Chagnac, A., Kirkpatrick, C. M., & Green, B. (2008). Lean body mass normalizes the effect of obesity on renal function. British Journal of Clinical Pharmacology, 65(6), 964–965. doi:10.1111/j.1365-2125.2008.03112.x.

    PubMed  PubMed Central  Article  Google Scholar 

  • Jenke, A., Freiberg-Richter, J., Johne, C., Knoth, H., Schleyer, E., Ehninger, G., et al. (2005). Targeting once-daily intravenous busulfan in combination with fludarabine before allogeneic hematopoietic cell transplantation. Bone Marrow Transplantation, 35(6), 627–628.

    CAS  PubMed  Article  Google Scholar 

  • Kaddurah-Daouk, R., Weinshilboum, R. M., & Pharmacometabolomics Research, N. (2014). Pharmacometabolomics: implications for clinical pharmacology and systems pharmacology. Clinical Pharmacology and Therapeutics, 95(2), 154–167. doi:10.1038/clpt.2013.217.

    CAS  PubMed  Article  Google Scholar 

  • Kaddurah-Daouk, R., Weinshilboum, R., & Pharmacometabolomics Research, N. (2015). Metabolomic signatures for drug response phenotypes: Pharmacometabolomics enables precision medicine. Clinical Pharmacology and Therapeutics, 98(1), 71–75. doi:10.1002/cpt.134.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Martin, P., Riley, R., Back, D. J., & Owen, A. (2008). Comparison of the induction profile for drug disposition proteins by typical nuclear receptor activators in human hepatic and intestinal cells. British Journal of Pharmacology, 153(4), 805–819. doi:10.1038/sj.bjp.0707601.

    CAS  PubMed  Article  Google Scholar 

  • McCune, J. S., & Holmberg, L. A. (2009). Busulfan in hematopoietic stem cell transplant setting. Expert Opinion on Drug Metabolism & Toxicology, 5(8), 957–969. doi:10.1517/17425250903107764.

    CAS  Article  Google Scholar 

  • McCune, J. S., Batchelder, A., Deeg, H. J., Gooley, T., Cole, S., Phillips, B., et al. (2007). Cyclophosphamide following targeted oral busulfan as conditioning for hematopoietic cell transplantation: Pharmacokinetics, liver toxicity, and mortality. Biology of Blood and Marrow Transplantation, 13(7), 853–862.

    CAS  PubMed  Article  Google Scholar 

  • McCune, J. S., Woodahl, E. L., Furlong, T., Storer, B., Wang, J., Heimfeld, S., et al. (2012). A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients. Cancer Chemotherapy and Pharmacology, 69(1), 263–272. doi:10.1007/s00280-011-1736-3.

    CAS  PubMed  Article  Google Scholar 

  • McCune, J. S., Baker, K. S., Blough, D. K., Gamis, A., Bemer, M. J., Kelton-Rehkopf, M. C., et al. (2013). Variation in prescribing patterns and therapeutic drug monitoring of intravenous busulfan in pediatric hematopoietic cell transplant recipients. Journal of Clinical Pharmacology, 53(3), 264–275. doi:10.1177/0091270012447196.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • McCune, J. S., Bemer, M. J., Barrett, J. S., Scott Baker, K., Gamis, A. S., & Holford, N. H. (2014). Busulfan in infant to adult hematopoietic cell transplant recipients: A population pharmacokinetic model for initial and bayesian dose personalization. Clinical Cancer Research, 20(3), 754–763. doi:10.1158/1078-0432.CCR-13-1960.

    CAS  PubMed  Article  Google Scholar 

  • Mitamura, K., Hori, N., Iida, T., Suzuki, M., Shimizu, T., Nittono, H., et al. (2011). Identification of S-acyl glutathione conjugates of bile acids in human bile by means of LC/ESI-MS. Steroids, 76(14), 1609–1614. doi:10.1016/j.steroids.2011.10.001.

    CAS  PubMed  Article  Google Scholar 

  • Morales-Ramirez, P., Miranda-Pasaye, S., Cruz-Vallejo, V. L., Vallarino-Kelly, T., & Mendiola-Cruz, M. T. (2006). Kinetic of genotoxic expression in the pharmacodynamics of busulfan. Archives of Medical Research, 37(3), 316–321. doi:10.1016/j.arcmed.2005.06.014.

    CAS  PubMed  Article  Google Scholar 

  • Nadkarni, M. V., Trams, E. G., & Smith, P. K. (1959). Preliminary studies on the distribution and fate of TEM, TEPA, and myeleran in the human. Cancer Research, 19, 713–718.

    CAS  PubMed  Google Scholar 

  • Nicholson, J. K., Connelly, J., Lindon, J. C., & Holmes, E. (2002). Metabonomics: A platform for studying drug toxicity and gene function. Nature Reviews Drug Discovery, 1(2), 153–161. doi:10.1038/nrd728.

    CAS  PubMed  Article  Google Scholar 

  • Nieder, M. L., McDonald, G. B., Kida, A., Hingorani, S., Armenian, S. H., Cooke, K. R., et al. (2011). National Cancer Institute-National Heart, Lung and Blood Institute/pediatric Blood and Marrow Transplant Consortium First International Consensus Conference on late effects after pediatric hematopoietic cell transplantation: long-term organ damage and dysfunction. Biology of Blood and Marrow Transplantation, 17(11), 1573–1584. doi:10.1016/j.bbmt.2011.09.013.

    PubMed  PubMed Central  Article  Google Scholar 

  • Poonkuzhali, B., Chandy, M., Srivastava, A., Dennison, D., & Krishnamoorthy, R. (2001). Glutathione S-transferase activity influences busulfan pharmacokinetics in patients with beta thalassemia major undergoing bone marrow transplantation. Drug Metabolism and Disposition, 29(3), 264–267.

    CAS  PubMed  Google Scholar 

  • Radich, J. P., Gooley, T., Bensinger, W., Chauncey, T., Clift, R., Flowers, M., et al. (2003). HLA-matched related hematopoietic cell transplantation for chronic-phase CML using a targeted busulfan and cyclophosphamide preparative regimen. Blood, 102(1), 31–35.

    CAS  PubMed  Article  Google Scholar 

  • Randolph, T. W., Harezlak, J., & Feng, Z. (2012). Structured penalties for functional linear models-partially empirical eigenvectors for regression. Electronic Journal of Statistics, 6, 323–353. doi:10.1214/12-ejs676.

    PubMed  PubMed Central  Article  Google Scholar 

  • Rezvani, A. R., McCune, J. S., Storer, B. E., Batchelder, A., Kida, A., Deeg, H. J., et al. (2013). Cyclophosphamide followed by intravenous targeted busulfan for allogeneic hematopoietic cell transplantation: Pharmacokinetics and clinical outcomes. Biology of Blood and Marrow Transplantation, 19(7), 1033–1039. doi:10.1016/j.bbmt.2013.04.005.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Rotroff, D. M., Oki, N. O., Liang, X., Yee, S. W., Stocker, S. L., Corum, D. G., et al. (2016). Pharmacometabolomic assessment of metformin in non-diabetic, African Americans. Frontiers in Pharmacology, 7, 135. doi:10.3389/fphar.2016.00135.

    PubMed  PubMed Central  Article  Google Scholar 

  • Singh, S. V., Leal, T., & Awasthi, Y. C. (1988). Inhibition of human glutathione S-transferases by bile acids. Toxicology and Applied Pharmacology, 95(2), 248–254.

    CAS  PubMed  Article  Google Scholar 

  • Smith, C. A., Want, E. J., O’Maille, G., Abagyan, R., & Siuzdak, G. (2006). XCMS: Processing mass spectrometry data for metabolite profiling using nonlinear peak alignment, matching, and identification. Analytical Chemistry, 78(3), 779–787. doi:10.1021/ac051437y.

    CAS  PubMed  Article  Google Scholar 

  • Tarantal, A. F., Giannoni, F., Lee, C. C., Wherley, J., Sumiyoshi, T., Martinez, M., et al. (2012). Nonmyeloablative conditioning regimen to increase engraftment of gene-modified hematopoietic stem cells in young rhesus monkeys. Molecular Therapy, 20(5), 1033–1045. doi:10.1038/mt.2011.312.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Tautenhahn, R., Bottcher, C., & Neumann, S. (2008). Highly sensitive feature detection for high resolution LC/MS. BMC Bioinformatics, 9, 504. doi:10.1186/1471-2105-9-504.

    PubMed  PubMed Central  Article  Google Scholar 

  • Tay-Sontheimer, J., Shireman, L. M., Beyer, R. P., Senn, T., Witten, D., Pearce, R. E., et al. (2014). Detection of an endogenous urinary biomarker associated with CYP2D6 activity using global metabolomics. Pharmacogenomics, 15(16), 1947–1962. doi:10.2217/pgs.14.155.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Vodopick, H., Hamilton, H. E., Jackson, H. L., Peng, C. T., & Sheets, R. F. (1969). Metabolic fate of tritiated busulfan in man. Journal of Laboratory and Clinical Medicine, 73(2), 266–276.

    CAS  PubMed  Google Scholar 

  • Wang, Y. M., Ong, S. S., Chai, S. C., & Chen, T. (2012). Role of CAR and PXR in xenobiotic sensing and metabolism. Expert Opinion on Drug Metabolism & Toxicology, 8(7), 803–817. doi:10.1517/17425255.2012.685237.

    CAS  Article  Google Scholar 

  • Xu, J., Chen, Y., Zhang, R., Song, Y., Cao, J., Bi, N., et al. (2013). Global and targeted metabolomics of esophageal squamous cell carcinoma discovers potential diagnostic and therapeutic biomarkers. Molecular and Cellular Proteomics, 12(5), 1306–1318. doi:10.1074/mcp.M112.022830.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Yeh, R. F., Pawlikowski, M. A., Blough, D. K., McDonald, G. B., O’Donnell, P. V., Rezvani, A., et al. (2012). Accurate targeting of daily intravenous busulfan with 8 h blood sampling in hospitalized adult hematopoietic cell transplant recipients. Biology of Blood and Marrow Transplantation, 18(2), 265–272. doi:10.1016/j.bbmt.2011.06.013.

    CAS  PubMed  Article  Google Scholar 

  • Zwaveling, J., Press, R. R., Bredius, R. G., van Derstraaten, T. R., den Hartigh, J., Bartelink, I. H., et al. (2008). Glutathione S-transferase polymorphisms are not associated with population pharmacokinetic parameters of busulfan in pediatric patients. Therapeutic Drug Monitoring, 30(4), 504–510.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank the study subjects, their caregivers, and the patient care staff for their support of this study. This work was supported by research funding from the National Institute of Health (CA182963, ES07033, CA18029, and CA15704).

Funding

This study was funded by the National Institute of Health (CA182963, ES07033, CA18029, and CA15704).

Author information

Affiliations

  1. Department of Pharmaceutics, University of Washington, Seattle, WA, USA

    Yvonne S. Lin, Savannah J. Kerr, Laura M. Shireman, Tauri Senn & Jeannine S. McCune

  2. Pharmacokinetics Laboratory, Department of Pharmacy, University of Washington, Box 357630, Seattle, WA, 98195, USA

    Jeannine S. McCune

  3. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Timothy Randolph & Jeannine S. McCune

Authors
  1. Yvonne S. Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Savannah J. Kerr
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Timothy Randolph
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laura M. Shireman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tauri Senn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jeannine S. McCune
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeannine S. McCune.

Ethics declarations

Conflict of Interest

All authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human subjects were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 358 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lin, Y.S., Kerr, S.J., Randolph, T. et al. Prediction of intravenous busulfan clearance by endogenous plasma biomarkers using global pharmacometabolomics. Metabolomics 12, 161 (2016). https://doi.org/10.1007/s11306-016-1106-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11306-016-1106-6

Keywords

  • Pharmacometabolomics
  • Pharmacokinetics
  • Busulfan
  • Biomarkers
  • Hematopoietic cell transplantation
  • Personalized medicine