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Prospective validation of a novel IV busulfan fixed dosing for paediatric patients to improve therapeutic AUC targeting without drug monitoring

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Abstract

Introduction

Oral busulfan clearance is age-dependent and children experience a wide variability in plasma exposure. BSA- or age-based dosing is used with therapeutic drug monitoring (TDM) to reduce this variability.

Purpose

A new intravenous (IV) dosing of busulfan (Bu) based on body weight, designed to improve AUC targeting without TDM and dose-adjustment, was prospectively evaluated.

Method

Bu was administered as a 2 h IV infusion every 6 h over 4 days (16 administrations). Five dose levels were defined on body weight as follows: 1.0 mg/kg for <9 kg; 1.2 mg/kg for 9 to <16 kg; 1.1 mg/kg for 16–23 kg; 0.95 mg/kg for >23–34 kg; 0.80 mg/kg for >34 kg. Bu treatment was followed by Cyclophosphamide or Melphalan prior to allogeneic or autologous transplantation in 55 children aged 0.3–17.2 years (median 5.6 years).

Results

No difference in AUC values was observed between weight strata (mean ± SD 1248 ± 205 μmol·min), whereas a significant difference in Bu clearance was demonstrated. This new dosing enabled to achieve a mean exposure comparable to that in adults. At dose 1, 91% of patients achieved the targeted AUC range (900–1500 μmol·min) while no patients were underexposed. At doses 9 and 13, over 75% of patients remained within that target whilst most of the others were slightly above. Successful engraftment was achieved in all patients. In conclusion, from infants to adults this new dosing enabled, without TDM and dose adjustment, to successfully target a therapeutic AUC window.

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References

  1. Andersson BS, Kashyap A, Gian V, Wingard JR, Fernandez H, Cagnoni PJ, et al (2002) Conditioning therapy with intravenous busulfan and cyclophosphamide (IV BuCy2) for hematologic malignancies prior to allogeneic stem cell transplantation: a phase II study. Biol Blood Marrow Transplant 8(3):145–154

    Article  PubMed  CAS  Google Scholar 

  2. Andersson BS, Thall PF, Madden T, Couriel D, Wang X, Tran HT, et al (2002) Busulfan systemic exposure relative to regimen-related toxicity and acute graft-versus-host disease: defining a therapeutic window for i.v. BuCy2 in chronic myelogenous leukemia Biol Blood Marrow Transplant 8(9):477–485

    Article  PubMed  CAS  Google Scholar 

  3. Andersson BS, Madden T, Tran HT, Hu WW, Blume KG, Chow DSL, et al (2000) Acute safety and pharmacokinetics of intravenous busulfan when used with oral busulfan and cyclosphosphamide as pretransplantation conditioning therapy: a phase I study. Biol Blood Marrow Transplant 6:548–554

    Article  PubMed  CAS  Google Scholar 

  4. Bleyzac N, Souillet G, Magron P, Janoly A, Martin P, Bertrand Y, et al (2001) Improved clinical outcome of paediatric bone marrow recipients using a test dose and Bayesian pharmacokinetic individualization of busulfan dosage regimens. Bone Marrow Transplant 28(8):743–751

    Article  PubMed  CAS  Google Scholar 

  5. Bolinger AM, Zangwill AB, Slattery JT, Risler LJ, Sultan DH, Glidden DV, et al (2001) Target dose adjustment of busulfan in pediatric patients undergoing bone marrow transplantation. Bone Marrow Transplant 28(11):1013–1018

    Article  PubMed  CAS  Google Scholar 

  6. Bostrom B, Enockson K, Johnson A, Bruns A, Blazar B (2003) Plasma pharmacokinetics of high-dose oral busulfan in children and adults undergoing bone marrow transplantation. Pediatr Transplant 7(Suppl 3):12–18

    Article  PubMed  Google Scholar 

  7. Bouligand J, Boland I, Valteau-Couanet D, Deroussent A, Kalifa C, Hartmann O, et al (2003) In children and adolescents, the pharmacodynamics of high-dose busulfan is dependent on the second alkylating agent used in the combined regimen (melphalan or thiotepa). Bone Marrow Transplant 32(10):979–986

    Article  PubMed  CAS  Google Scholar 

  8. Chan SC, Liu CL, Lo CM, Lam BK, Lee EW, Wong Y, et al (2006) Estimating liver weight of adults by body weight and gender. World J Gastroenterol 12(14):2217–2222

    PubMed  Google Scholar 

  9. Chan YL, Li CK, Chik KW, Law MY, Howard R (2005) Liver volume in thalassaemia major: relationship with body weight, serum ferritin, and liver function. Pediatr Radiol 35(2):165–168

    Article  PubMed  Google Scholar 

  10. Copelan EA, Bechtel TP, Avalos BR, Elder PJ, Ezzone SA, Scholl MD, et al (2001) Busulfan levels are influenced by prior treatment and are associated with hepatic veno-occlusive disease and early mortality but not with delayed complications following marrow transplantation. Bone Marrow Transplant 27(11):1121–1124

    Article  PubMed  CAS  Google Scholar 

  11. Dalle JH, Wall D, Theoret Y, Duval M, Shaw L, Larocque D, et al (2003) Intravenous busulfan for allogeneic hematopoietic stem cell transplantation in infants: clinical and pharmacokinetic results. Bone Marrow Transplant 32(7):647–651

    Article  PubMed  CAS  Google Scholar 

  12. De Paepe ME, Carr SR, Cassese JA (2003) Postmortem validation of imaging-derived formulas for prediction of fetal lung volume. Fetal Diagn Ther 18(5):353–359

    Article  PubMed  Google Scholar 

  13. Dix SP, Wingard JR, Mullins RE, Jerkunica I, Davidson TG, Gilmore CE, et al (1996) Association of busulfan area under the curve with veno-occlusive disease following BMT. Bone Marrow Transplant 17(2):225–230

    PubMed  CAS  Google Scholar 

  14. European Agency for the Evaluation of Medicinal Products HMEU (1997) Note for guidance on clinical investigation of medicinal products in children. CPMP/EWP/462/95

  15. Food and Drug Administration (FDA) CfDERC (1998) General considerations for pediatric pharmacokinetic studies for drugs and biological products. Guidance for Industry (draft)

  16. Gibbs JP, Liacouras CA, Baldassano RN, Slattery JT (1999) Up-regulation of glutathione S-transferase activity in enterocytes of young children. Drug Metab Dispos 27(12):1466–1469

    PubMed  CAS  Google Scholar 

  17. Gibbs JP, Murray G, Risler L, Chien JY, Dev R, Slattery JT (1997) Age-dependent tetrahydrothiophenium ion formation in young children and adults receiving high-dose busulfan. Cancer Res 57(24):5509–5516

    PubMed  CAS  Google Scholar 

  18. Grimley MS, Taylor C, Wall DA (2004) Frequency and magnitude of dose adjustment of i.v. busulfan in targeted dosing strategy for pediatrc allogeneic transplantation Bone Marrow Transplant 10:78

    Google Scholar 

  19. Grochow LB, Jones RJ, Brundrett RB, Braine HG, Chen TL, Saral R, et al (1989) Pharmacokinetics of busulfan: correlation with veno-occlusive disease in patients undergoing bone marrow transplantation. Cancer Chemother Pharmacol 25(1):55–61

    Article  PubMed  CAS  Google Scholar 

  20. Grochow LB (1993) Busulfan disposition: the role of therapeutic monitoring in bone marrow transplantation induction regimens. Semin Oncol 20(4 Suppl 4):18–25

    PubMed  CAS  Google Scholar 

  21. Hassan M, Ljungman P, Bolme P, Ringden O, Syruckova Z, Bekassy A, et al (1994) Busulfan bioavailability. Blood 84(7):2144–2150

    PubMed  CAS  Google Scholar 

  22. Hassan M, Oberg G, Bekassy AN, Aschan J, Ehrsson H, Ljungman P, et al (1991) Pharmacokinetics of high-dose busulphan in relation to age and chronopharmacology. Cancer Chemother Pharmacol 28(2):130–134

    Article  PubMed  CAS  Google Scholar 

  23. Johnson TN, Tucker GT, Tanner MS, Rostami-Hodjegan A (2005) Changes in liver volume from birth to adulthood: a meta-analysis. Liver Transpl 11(12):1481–1493

    Article  PubMed  Google Scholar 

  24. Jones RJ, Lee KSK, Beschorner WE (1987) Veno-occlusive disease of the liver following bone marrow transplantation. Transplantation 44:778–783

    Article  PubMed  CAS  Google Scholar 

  25. Kashyap A, Wingard J, Cagnoni P, Roy J, Tarantolo S, Hu W, et al (2002) Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality. Biol Blood Marrow Transplant 8(9):493–500

    Article  PubMed  CAS  Google Scholar 

  26. Krivoy N, Hoffer E, Tabak A, Elhasid R, Arush MW, Stein J, et al (2002) Therapeutic monitoring of busulfan in pediatric bone marrow transplantation. Pediatr Hematol Oncol 19(1):31–37

    Article  PubMed  CAS  Google Scholar 

  27. Lee JH, Choi SJ, Lee JH, Kim SE, Park CJ, Chi HS, et al (2005) Decreased incidence of hepatic veno-occlusive disease and fewer hemostatic derangements associated with intravenous busulfan vs oral busulfan in adults conditioned with busulfan + cyclophosphamide for allogeneic bone marrow transplantation. Ann Hematol 84(5):321–330

    Article  PubMed  CAS  Google Scholar 

  28. Lindley C, Shea T, McCune J, Shord S, Decker J, Harvey D, et al (2004) Intraindividual variability in busulfan pharmacokinetics in patients undergoing a bone marrow transplant: assessment of a test dose and first dose strategy. Anticancer Drugs 15(5):453–459

    Article  PubMed  CAS  Google Scholar 

  29. Ljungman P, Hassan M, Bekassy AN, Ringden O, Oberg G (1997) High busulfan concentrations are associated with increased transplant-related mortality in allogeneic bone marrow transplant patients. Bone Marrow Transplant 20(11):909–913

    Article  PubMed  CAS  Google Scholar 

  30. McCune JS, Gooley T, Gibbs JP, Sanders JE, Petersdorf EW, Appelbaum FR, et al (2002) Busulfan concentration and graft rejection in pediatric patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 30(3):167–173

    Article  PubMed  CAS  Google Scholar 

  31. McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M, et al (1993) Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 118(4):255–267

    PubMed  CAS  Google Scholar 

  32. Nguyen L, Fuller D, Lennon S, Leger F, Puozzo C (2004) I.V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients. Bone Marrow Transplant 33(10):979–987

    Article  PubMed  CAS  Google Scholar 

  33. Nguyen L, Leger F, Lennon S, Puozzo C (2006) Intravenous busulfan in adults prior to haematopoietic stem cell transplantation: a population pharmacokinetic study. Cancer Chemother Pharmacol 57(2):191–198

    Article  PubMed  CAS  Google Scholar 

  34. Nguyen L (2006) The impact of switching from oral to IV busulfan on haematopoietic stem cell transplantation. EJHP Practice 12:58–59

    Google Scholar 

  35. Noda T, Todani T, Watanabe Y, Yamamoto S (1997) Liver volume in children measured by computed tomography. Pediatr Radiol 27(3):250–252

    Article  PubMed  CAS  Google Scholar 

  36. Oechtering D, Schiltmeyer B, Hempel G, Schwab M, Wurthwein G, Murdter T, et al (2005) Toxicity and pharmacokinetics of i.v. busulfan in children before stem cell transplantation. Anticancer Drugs 16(3):337–344

    Article  PubMed  CAS  Google Scholar 

  37. Pawlowska AB, Blazar BR, Angelucci E, Baronciani D, Shu XO, Bostrom B (1997) Relationship of plasma pharmacokinetics of high-dose oral busulfan to the outcome of allogeneic bone marrow transplantation in children with thalassemia. Bone Marrow Transplant 20(11):915–920

    Article  PubMed  CAS  Google Scholar 

  38. Poonkuzhali B, Srivastava A, Quernin MH, Dennison D, Aigrain EJ, Kanagasabapathy AS, et al (1999) Pharmacokinetics of oral busulphan in children with beta thalassaemia major undergoing allogeneic bone marrow transplantation. Bone Marrow Transplant 24(1):5–11

    Article  PubMed  CAS  Google Scholar 

  39. Schuler US, Renner UD, Kroschinsky F, Johne C, Jenke A, Naumann R, et al (2001) Intravenous busulphan for conditioning before autologous or allogeneic human blood stem cell transplantation. Br J Haematol 114(4):944–950

    Article  PubMed  CAS  Google Scholar 

  40. Slattery JT, Clift RA, Buckner CD, Radich J, Storer B, Bensinger WI, et al (1997) Marrow transplantation for chronic myeloid leukemia: the influence of plasma busulfan levels on the outcome of transplantation. Blood 89(8):3055–3060

    PubMed  CAS  Google Scholar 

  41. Slattery JT, Risler LJ (1998) Therapeutic monitoring of busulfan in hematopoietic stem cell transplantation. Ther Drug Monit 20(5):543–549

    Article  PubMed  CAS  Google Scholar 

  42. Slattery JT, Sanders JE, Buckner CD, Schaffer RL, Lambert KW, Langer FP, et al (1995) Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics. Bone Marrow Transplant 16(1):31–42

    PubMed  CAS  Google Scholar 

  43. Sobocinski KA, Thall PF, Bekele N (2004) Matched pairs analysis of IV vs. PO busulfan as a conditioning agent prior to transplantation. Blood (ASH Annual Meeting) 104, Abst. 349

  44. Thall PF, Champlin RE, Andersson BS (2004) Comparison of 100-day mortality rates associated with i.v. busulfan and cyclophosphamide vs. other preparative regimens in allogeneic bone marrow transplantation for chronic myelogenous leukemia: Bayesian sensitivity analyses of confounded treatment and center effects. Bone Marrow Transplant 33(12):1191–1199

    Article  PubMed  CAS  Google Scholar 

  45. Tran H, Petropoulos D, Worth L, Mullen CA, Madden T, Andersson B, et al (2004) Pharmacokinetics and individualized dose adjustment of intravenous busulfan in children with advanced hematologic malignancies undergoing allogeneic stem cell transplantation. Biol Blood Marrow Transplant 10(11):805–812

    Article  PubMed  CAS  Google Scholar 

  46. Vassal G, Deroussent A, Challine D, Hartmann O, Koscielny S, Valteau-Couanet D, et al (1992) Is 600 mg/m2 the appropriate dosage of busulfan in children undergoing bone marrow transplantation? Blood 79(9):2475–2479

    PubMed  CAS  Google Scholar 

  47. Vassal G, Koscielny S, Challine D, Valteau-Couanet D, Boland I, Deroussent A, et al (1996) Busulfan disposition and hepatic veno-occlusive disease in children undergoing bone marrow transplantation. Cancer Chemother Pharmacol 37(3):247–253

    Article  PubMed  CAS  Google Scholar 

  48. Vassal G, Mery-Mignard D, Caulin C (2003) Clinical trials in paediatric oncology. Recommendations for the development of new anticancer agents. Therapie 58(3):229–246

    Article  PubMed  Google Scholar 

  49. Vassal G, Tranchand B, Valteau-Couanet D, Mahe C, Couanet D, Schoeppfer C, et al (2001) Pharmacodynamics of tandem high-dose melphalan with peripheral blood stem cell transplantation in children with neuroblastoma and medulloblastoma. Bone Marrow Transplant 27(5):471–477

    Article  PubMed  CAS  Google Scholar 

  50. Vassal G (1994) Pharmacologically-guided dose adjustment of busulfan in high-dose chemotherapy regimens: rationale and pitfalls (review). Anticancer Res 14(6A):2363–2370

    PubMed  CAS  Google Scholar 

  51. Wall DA, Chan KW, Klemperer MR (1999) Phase II trial of intravenous busulfan (IV BU) and cyclophosphamide (Cy) in pediatric patients: preliminary pharmacokinetics. ASBMT, Abstract No. 80

  52. Yeager AM, Wagner JE Jr, Graham ML, Jones RJ, Santos GW, Grochow LB (1992) Optimization of busulfan dosage in children undergoing bone marrow transplantation: a pharmacokinetic study of dose escalation. Blood 80(9):2425–2428

    PubMed  CAS  Google Scholar 

  53. Yoshizumi T, Gondolesi GE, Bodian CA, Jeon H, Schwartz ME, Fishbein TM, et al (2003) A simple new formula to assess liver weight. Transplant Proc 35(4):1415–1420

    Article  PubMed  CAS  Google Scholar 

  54. Zwaveling J, Bredius RG, Cremers SC, Ball LM, Lankester AC, Teepe-Twiss IM, et al (2005) Intravenous busulfan in children prior to stem cell transplantation: study of pharmacokinetics in association with early clinical outcome and toxicity. Bone Marrow Transplant 35(1):17–23

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Dr. D. Frappaz and his team at Centre Léon Bérard, Lyon, France; Dr. F. Demeocq and his team at CHU Hôtel Dieu, Clermont-Ferrand, France; Prof. P. Bordigoni and his team at Hôpital Brabois – Enfants Malades, Vandoeuvre-les-Nancy, France; Prof. E. Vilmer and his team at Hôpital Robert Debré, Paris, for their participation in the trial. We also thank D. Fryer for her editorial assistance.

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Authors and Affiliations

  1. Institut Gustave Roussy, Villejuif, France

    G. Vassal & D. Valteau-Couanet

  2. Hôpital d’Enfants, La Timone, Marseille, France

    G. Michel & J. C. Gentet

  3. Hôpital St-Louis, Paris, France

    H. Espérou

  4. Institut Curie, Paris, France

    F. Doz

  5. CHU Hôtel-Dieu, Nantes, France

    F. Mechinaud

  6. Hôpital Debrousse, Lyon, France

    C. Galambrun

  7. Hôpital Necker-Enfants Malades, Paris, France

    B. Neven

  8. Institut de Recherche Pierre Fabre, Castres, France

    H. Zouabi, L. Nguyen & C. Puozzo

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  1. G. Vassal
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  2. G. Michel
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  3. H. Espérou
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  4. J. C. Gentet
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  5. D. Valteau-Couanet
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  10. H. Zouabi
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  11. L. Nguyen
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  12. C. Puozzo
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Correspondence to C. Puozzo.

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Vassal, G., Michel, G., Espérou, H. et al. Prospective validation of a novel IV busulfan fixed dosing for paediatric patients to improve therapeutic AUC targeting without drug monitoring. Cancer Chemother Pharmacol 61, 113–123 (2008). https://doi.org/10.1007/s00280-007-0455-2

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  • DOI: https://doi.org/10.1007/s00280-007-0455-2

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