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Intra-individual Pharmacokinetic Variability of Intravenous Busulfan in Hematopoietic Stem Cell-Transplanted Children

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Abstract

Background

Busulfan therapeutic drug monitoring (TDM) is necessary to better achieve the target exposure in children before hematopoietic stem cell transplantation (HSCT). However, TDM-based dosing may be challenging if intra-individual pharmacokinetic variability (also denoted inter-occasion variability [IOV]) occurs during therapy.

Objectives

The objectives of this study were to describe and quantify busulfan IOV in children, and to investigate its potential determinants.

Methods

We performed a new analysis of published data from children who received intravenous busulfan over 4 days before HSCT. We calculated individual pharmacokinetic parameters on each day of therapy using a published population pharmacokinetic model of busulfan and analyzed their changes. Population estimation of IOV was also performed with non-linear mixed effects (NLME) modeling. Potential predictors of significant decrease in busulfan clearance (CL) were assessed by using machine learning approaches.

Results

IOV could be assessed in 136 children. Between day (D) 1 and D2, most patients (80%) experienced a decrease in busulfan CL, with a median change of − 7.9%. However, both large decreases (minimum, −  48.5%) and increases in CL (maximum, + 44%) were observed. Over D1–D3 of therapy, mean CL significantly decreased (−  15%), with a decrease of ≥ 20% in 22% of patients. Some patients also showed unstable CL from day to day. NLME modeling of IOV provided a coefficient of variation of 10.6% and 13.1% for volume of distribution (Vd) and CL, respectively. Some determinants of significant decreases in busulfan CL were identified, but predictive performance of the models was limited.

Conclusions

Significant busulfan intra-individual variability may occur in children who receive a HSCT and is hardly predictable. The main risk is busulfan overexposure. Performing TDM repeatedly over therapy appears to be the best way to accurately estimate busulfan exposure and perform precision dosing.

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References

  1. Bartelink IH, Lalmohamed A, van Reij EM, Dvorak CC, Savic RM, Zwaveling J, et al. Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis. Lancet Haematol. 2016;3(11):e526–36. https://doi.org/10.1016/S2352-3026(16)30114-4.

    Article  Google Scholar 

  2. Nguyen L, Fuller D, Lennon S, Leger F, Puozzo CIV. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients. Bone Marrow Transpl. 2004;33(10):979–87. https://doi.org/10.1038/sj.bmt.1704446.

    Article  CAS  Google Scholar 

  3. Buffery PJ, Allen KM, Chin PK, Moore GA, Barclay ML, Begg EJ. Thirteen years’ experience of pharmacokinetic monitoring and dosing of busulfan: can the strategy be improved? Ther Drug Monit. 2014;36(1):86–92. https://doi.org/10.1097/FTD.0b013e31829dc940.

    Article  CAS  Google Scholar 

  4. Philippe M, Goutelle S, Guitton J, Fonrose X, Bergeron C, Girard P, et al. Should busulfan therapeutic range be narrowed in pediatrics? Experience from a large cohort of hematopoietic stem cell transplant children. Bone Marrow Transpl. 2016;51(1):72–8. https://doi.org/10.1038/bmt.2015.218.

    Article  CAS  Google Scholar 

  5. Choong E, Uppugunduri CRS, Marino D, Kuntzinger M, Doffey-Lazeyras F, Lo Piccolo R, et al. Therapeutic drug monitoring of busulfan for the management of pediatric patients: cross-validation of methods and long-term performance. Ther Drug Monit. 2018;40(1):84–92. https://doi.org/10.1097/FTD.0000000000000468.

    Article  CAS  Google Scholar 

  6. McCune JS, Baker KS, Blough DK, Gamis A, Bemer MJ, Kelton-Rehkopf MC, et al. Variation in prescribing patterns and therapeutic drug monitoring of intravenous busulfan in pediatric hematopoietic cell transplant recipients. J Clin Pharmacol. 2013;53(3):264–75. https://doi.org/10.1177/0091270012447196.

    Article  CAS  Google Scholar 

  7. Palmer J, McCune JS, Perales MA, Marks D, Bubalo J, Mohty M, et al. Personalizing busulfan-based conditioning: considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee. Biol Blood Marrow Transpl. 2016;22(11):1915–25. https://doi.org/10.1016/j.bbmt.2016.07.013.

    Article  CAS  Google Scholar 

  8. Bleyzac N, Souillet G, Magron P, Janoly A, Martin P, Bertrand Y, et al. Improved clinical outcome of paediatric bone marrow recipients using a test dose and Bayesian pharmacokinetic individualization of busulfan dosage regimens. Bone Marrow Transpl. 2001;28(8):743–51. https://doi.org/10.1038/sj.bmt.1703207.

    Article  CAS  Google Scholar 

  9. Neely M, Philippe M, Rushing T, Fu X, van Guilder M, Bayard D, et al. Accurately achieving target busulfan exposure in children and adolescents with very limited sampling and the BestDose Software. Ther Drug Monit. 2016;38(3):332–42. https://doi.org/10.1097/FTD.0000000000000276.

    Article  CAS  Google Scholar 

  10. Philippe M, Neely M, Rushing T, Bertrand Y, Bleyzac N, Goutelle S. Maximal concentration of intravenous busulfan as a determinant of veno-occlusive disease: a pharmacokinetic-pharmacodynamic analysis in 293 hematopoietic stem cell transplanted children. Bone Marrow Transpl. 2019;54(3):448–57. https://doi.org/10.1038/s41409-018-0281-7.

    Article  CAS  Google Scholar 

  11. Busilvex summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/busilvex-epar-product-information_en.pdf. Accessed 6 Sep 2019.

  12. Neely MN, van Guilder MG, Yamada WM, Schumitzky A, Jelliffe RW. Accurate detection of outliers and subpopulations with Pmetrics, a nonparametric and parametric pharmacometric modeling and simulation package for R. Ther Drug Monit. 2012;34(4):467–76. https://doi.org/10.1097/FTD.0b013e31825c4ba6.

    Article  Google Scholar 

  13. Breiman L, Friedman J, Stone CJ, Olshen RA. Classification and regression trees. Boca Raton: Chapman and Hall/CRC; 1984.

    Google Scholar 

  14. Traub SL, Johnson CE. Comparison of methods of estimating creatinine clearance in children. Am J Hosp Pharm. 1980;37(2):195–201.

    CAS  Google Scholar 

  15. Jensen FV, Nielsen TD. Bayesian networks and decision graphs. New York: Springer Science; 2007.

    Book  Google Scholar 

  16. Spiegelhalter DJ, Dawid AP, Lauritzen SL, Cowell RG. Bayesian analysis in expert systems. Stat Sci. 1993;8(3):219–47.

    Article  Google Scholar 

  17. Lee JW, Kang HJ, Lee SH, Yu KS, Kim NH, Yuk YJ, et al. Highly variable pharmacokinetics of once-daily intravenous busulfan when combined with fludarabine in pediatric patients: phase I clinical study for determination of optimal once-daily busulfan dose using pharmacokinetic modeling. Biol Blood Marrow Transpl. 2012;18(6):944–50. https://doi.org/10.1016/j.bbmt.2011.11.025.

    Article  CAS  Google Scholar 

  18. Trame MN, Bergstrand M, Karlsson MO, Boos J, Hempel G. Population pharmacokinetics of busulfan in children: increased evidence for body surface area and allometric body weight dosing of busulfan in children. Clin Cancer Res. 2011;17(21):6867–77. https://doi.org/10.1158/1078-0432.CCR-11-0074.

    Article  CAS  Google Scholar 

  19. Paci A, Vassal G, Moshous D, Dalle JH, Bleyzac N, Neven B, et al. Pharmacokinetic behavior and appraisal of intravenous busulfan dosing in infants and older children: the results of a population pharmacokinetic study from a large pediatric cohort undergoing hematopoietic stem-cell transplantation. Ther Drug Monit. 2012;34(2):198–208. https://doi.org/10.1097/FTD.0b013e31824c2f60.

    Article  CAS  Google Scholar 

  20. Bartelink IH, Boelens JJ, Bredius RG, Egberts AC, Wang C, Bierings MB, et al. Body weight-dependent pharmacokinetics of busulfan in paediatric haematopoietic stem cell transplantation patients: towards individualized dosing. Clin Pharmacokinet. 2012;51(5):331–45. https://doi.org/10.2165/11598180-000000000-00000.

    Article  CAS  Google Scholar 

  21. Diestelhorst C, Boos J, McCune JS, Hempel G. Population pharmacokinetics of intravenous busulfan in children: revised body weight-dependent NONMEM® model to optimize dosing. Eur J Clin Pharmacol. 2014;70(7):839–47. https://doi.org/10.1007/s00228-014-1692-z.

    Article  Google Scholar 

  22. McCune JS, Bemer MJ, Barrett JS, Scott Baker K, Gamis AS, Holford NH. Busulfan in infant to adult hematopoietic cell transplant recipients: a population pharmacokinetic model for initial and Bayesian dose personalization. Clin Cancer Res. 2014;20(3):754–63. https://doi.org/10.1158/1078-0432.CCR-13-1960.

    Article  CAS  Google Scholar 

  23. Rhee SJ, Lee JW, Yu KS, Hong KT, Choi JY, Hong CR, et al. Pediatric patients undergoing hematopoietic stem cell transplantation can greatly benefit from a novel once-daily intravenous busulfan dosing nomogram. Am J Hematol. 2017;92(7):607–13. https://doi.org/10.1002/ajh.24734.

    Article  CAS  Google Scholar 

  24. Nava T, Kassir N, Rezgui MA, Uppugunduri CRS, Huezo-Diaz Curtis P, Duval M, et al. Incorporation of GSTA1 genetic variations into a population pharmacokinetic model for IV busulfan in paediatric hematopoietic stem cell transplantation. Br J Clin Pharmacol. 2018;84(7):1494–504. https://doi.org/10.1111/bcp.13566.

    Article  CAS  Google Scholar 

  25. Long-Boyle JR, Savic R, Yan S, Bartelink I, Musick L, French D, et al. Population pharmacokinetics of busulfan in pediatric and young adult patients undergoing hematopoietic cell transplant: a model-based dosing algorithm for personalized therapy and implementation into routine clinical use. Ther Drug Monit. 2015;37(2):236–45. https://doi.org/10.1097/FTD.0000000000000131.

    Article  CAS  Google Scholar 

  26. Lindley C, Shea T, McCune J, Shord S, Decker J, Harvey D, et al. Intraindividual variability in busulfan pharmacokinetics in patients undergoing a bone marrow transplant: assessment of a test dose and first dose strategy. Anticancer Drugs. 2004;15(5):453–9.

    Article  CAS  Google Scholar 

  27. Yeh RF, Pawlikowski MA, Blough DK, McDonald GB, O’Donnell PV, Rezvani A, et al. Accurate targeting of daily intravenous busulfan with 8-hour blood sampling in hospitalized adult hematopoietic cell transplant recipients. Biol Blood Marrow Transpl. 2012;18(2):265–72. https://doi.org/10.1016/j.bbmt.2011.06.013.

    Article  CAS  Google Scholar 

  28. Ansari M, Curtis PH, Uppugunduri CRS, Rezgui MA, Nava T, Mlakar V, et al. GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study. Oncotarget. 2017;8(53):90852–67. https://doi.org/10.18632/oncotarget.20310.

    Article  Google Scholar 

  29. Myers AL, Kawedia JD, Champlin RE, Kramer MA, Nieto Y, Ghose R, et al. Clarifying busulfan metabolism and drug interactions to support new therapeutic drug monitoring strategies: a comprehensive review. Expert Opin Drug Metab Toxicol. 2017;13(9):901–23. https://doi.org/10.1080/17425255.2017.1360277.

    Article  CAS  Google Scholar 

  30. Nath CE, Earl JW, Pati N, Stephen K, Shaw PJ. Variability in the pharmacokinetics of intravenous busulphan given as a single daily dose to paediatric blood or marrow transplant recipients. Br J Clin Pharmacol. 2008;66(1):50–9. https://doi.org/10.1111/j.1365-2125.2008.03166.x.

    Article  CAS  Google Scholar 

  31. Hassan M, Oberg G, Bjorkholm M, Wallin I, Lindgren M. Influence of prophylactic anticonvulsant therapy on high-dose busulphan kinetics. Cancer Chemother Pharmacol. 1993;33(3):181–6. https://doi.org/10.1007/bf00686213.

    Article  CAS  Google Scholar 

  32. Buggia I, Zecca M, Alessandrino EP, Locatelli F, Rosti G, Bosi A, et al. Itraconazole can increase systemic exposure to busulfan in patients given bone marrow transplantation. GITMO (Gruppo Italiano Trapianto di Midollo Osseo). Anticancer Res. 1996;16(4A):2083-8.

  33. Nilsson C, Aschan J, Hentschke P, Ringden O, Ljungman P, Hassan M. The effect of metronidazole on busulfan pharmacokinetics in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transpl. 2003;31(6):429–35. https://doi.org/10.1038/sj.bmt.1703896.

    Article  CAS  Google Scholar 

  34. Gulbis AM, Culotta KS, Jones RB, Andersson BS. Busulfan and metronidazole: an often forgotten but significant drug interaction. Ann Pharmacother. 2011;45(7–8):e39. https://doi.org/10.1345/aph.1Q087.

    Article  Google Scholar 

  35. Chung H, Yu KS, Hong KT, Choi JY, Hong CR, Kang HJ, et al. A significant influence of metronidazole on busulfan pharmacokinetics: a case report of therapeutic drug monitoring. Ther Drug Monit. 2017;39(3):208–10. https://doi.org/10.1097/FTD.0000000000000395.

    Article  CAS  Google Scholar 

  36. Harvey RD, Morgan ET. Cancer, inflammation, and therapy: effects on cytochrome p450-mediated drug metabolism and implications for novel immunotherapeutic agents. Clin Pharmacol Ther. 2014;96(4):449–57. https://doi.org/10.1038/clpt.2014.143.

    Article  CAS  Google Scholar 

  37. Sweiss K, Quigley JG, Oh A, Lee J, Ye R, Rondelli D, et al. A novel drug interaction between busulfan and blinatumomab. J Oncol Pharm Pract. 2019;25(1):226–8. https://doi.org/10.1177/1078155217729745.

    Article  CAS  Google Scholar 

  38. Kim B, Lee JW, Hong KT, Yu KS, Jang IJ, Park KD, et al. Pharmacometabolomics for predicting variable busulfan exposure in paediatric haematopoietic stem cell transplantation patients. Sci Rep. 2017;7(1):1711. https://doi.org/10.1038/s41598-017-01861-7.

    Article  CAS  Google Scholar 

  39. McCune JS, Batchelder A, Deeg HJ, Gooley T, Cole S, Phillips B, et al. Cyclophosphamide following targeted oral busulfan as conditioning for hematopoietic cell transplantation: pharmacokinetics, liver toxicity, and mortality. Biol Blood Marrow Transpl. 2007;13(7):853–62. https://doi.org/10.1016/j.bbmt.2007.03.012.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Univ Lyon, Université Lyon 1, UMR CNRS 5558, Laboratoire de Biométrie et Biologie Evolutive, Villeurbanne, France

    Hanen Marsit & Sylvain Goutelle

  2. Université de Monastir, Faculté de Pharmacie, Monastir, Tunisia

    Hanen Marsit

  3. Institut d’Hématologie et d’Oncologie Pédiatrique, Lyon, France

    Michaël Philippe & Yves Bertrand

  4. Laboratory of Applied Pharmacokinetics and Bioinformatics, Division of Pediatric Infectious Diseases, Children’s Hospital Los Angeles and the University of Southern California, Los Angeles, CA, USA

    Michael Neely

  5. Pharmacy Department, Children’s Hospital Los Angeles and the University of Southern California, Los Angeles, CA, USA

    Teresa Rushing

  6. Service de Pharmacie, Hospices Civils de Lyon, Groupement Hospitalier Nord, Hôpital Pierre Garraud, 136 rue du Commandant Charcot, 69005, Lyon, France

    Michel Ducher, Vincent Leclerc, Nathalie Bleyzac & Sylvain Goutelle

  7. Univ Lyon, Université Lyon 1, EMR 3738 PK/PD Modeling in Oncology and Hematology, Lyon, France

    Michel Ducher, Vincent Leclerc, Jérôme Guitton & Nathalie Bleyzac

  8. Laboratoire de Pharmacologie et Toxicologie, Hospices Civils de Lyon, Groupement Hospitalier Sud, Lyon, France

    Jérôme Guitton

  9. Univ Lyon, Université Lyon 1, ISPB, Faculté de Pharmacie de Lyon, Lyon, France

    Sylvain Goutelle

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  1. Hanen Marsit
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  2. Michaël Philippe
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Correspondence to Sylvain Goutelle.

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Conflict of interest

Hanen Marsit, Michaël Philippe, Michael Neely, Teresa Rushing, Yves Bertrand, Michel Ducher, Vincent Leclerc, Jérôme Guitton, Nathalie Bleyzac, and Sylvain Goutelle have no conflicts of interest that are relevant to the content of this manuscript.

Funding

This study was carried out as part of our routine work, which is funded by the authors’ institutions.

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Marsit, H., Philippe, M., Neely, M. et al. Intra-individual Pharmacokinetic Variability of Intravenous Busulfan in Hematopoietic Stem Cell-Transplanted Children. Clin Pharmacokinet 59, 1049–1061 (2020). https://doi.org/10.1007/s40262-020-00877-z

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