Abstract
A population pharmacokinetic analysis was performed in 30 patients who received an intravenous busulfan and cyclophosphamide regimen before hematopoietic stem cell transplantation. Each patient received 0.8 mg/kg as a 2 h infusion every 6 h for 16 doses. A total of 690 concentration measurements were analyzed using the nonlinear mixed effect model (NONMEM) program. A one-compartment model with an additive error model as an intraindividual variability including an interoccasion variability (IOV) in clearance (CL) was sufficient to describe the concentration–time profile of busulfan. Actual body weight (ABW) was found to be the determinant for CL and the volume of distribution (V) according to NONMEM analysis. In this limited study, the age (range 7–53 years old; median, 30 years old) had no significant effect on busulfan pharmacokinetics. For a patient weighting 60 kg, the typical CL and V were estimated to be 8.87 l/h and 33.8 l, respectively. The interindividual variability of CL and V were 13.6 and 6.3%, respectively. The IOV (6.6%) in CL was estimated to be less than the intraindividual variability. These results indicate high interpatient and intrapatient consistency of busulfan pharmacokinetics after intravenous administration, which may eliminate the requirement for pharmacokinetic monitoring.
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References
Santos GW, Tutschka PJ, Brookmeyer R, Saral R, Beschorner WE, Bias WB et al. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med 1983; 309: 1347–1353.
Tutschka PJ, Copelan EK, Klein JP . Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen. Blood 1987; 70: 1382–1388.
Grochow LB, Jones RJ, Brundrett RB, Braine HG, Chen TL, Saral R et al. Pharmacokinetics of busulfan: correlation with veno-occlusive disease in patients undergoing bone marrow transplantation. Cancer Chemother Pharmacol 1989; 25: 55–61.
Dix SP, Wingard JR, Mullins RE, Jerkunica I, Davidson TG, Gilmore CE et al. Association of busulfan area under the curve with veno-occlusive disease following BMT. Bone Marrow Transplant 1996; 17: 225–230.
Hassan M, Oberg G, Bekassy AN, Aschan J, Ehrsson H, Ljungman P et al. Pharmacokinetics of high-dose busulphan in relation to age and chronopharmacology. Cancer Chemother Pharmacol 1991; 28: 130–134.
Slattery JT, Sanders JE, Buckner CD, Schaffer RL, Lambert KW, Langer FP et al. Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics. Bone Marrow Transplant 1995; 16: 31–42.
Vassal G, Challine D, Koscielny S, Hartmann O, Deroussent A, Boland I et al. Chronopharmacology of high-dose busulfan in children. Cancer Res 1993; 53: 1534–1537.
Gibbs JP, Gooley T, Corneau B, Murray G, Stewart P, Appelbaum FR et al. The impact of obesity and disease on busulfan oral clearance in adults. Blood 1999; 93: 4436–4440.
Gibbs JP, Murray G, Risler L, Chien JY, Dev R, Slattery JT . Age-dependent tetrahydrothiophenium ion formulation in young children and adults receiving high-dose busulfan. Cancer Res 1997; 57: 5509–5516.
Olavarria E, Hassan M, Eades A, Nilsson C, Timms A, Matthews J et al. A phase I/II study of multiple-dose intravenous busulfan as myeloablation prior to stem cell transplantation. Leukemia 2000; 14: 1954–1959.
Andersson BS, Madden T, Tran HT, Hu WW, Blume KG, Chow DS et al. Acute safety and pharmacokinetics of intravenous busulfan when used with oral busulfan and cyclophosphamide as pretransplantation conditioning therapy: a phase I study. Biol Blood Marrow Transplant 2000; 6: 548–554.
Andersson BS, Kashyap A, Gian V, Wingard JR, Fernandez H, Cagnoni PJ et al. 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 2002; 8: 145–154.
Nguyen L, Fuller D, Lennon S, Leger F, Puozzo C . I.V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients. Bone Marrow Transplant 2004; 33: 979–987.
Vassal G, Re M, Gouyette A . Gas chromatographic-mass spectrometric assay for busulfan in biological fluids using a deuterated internal standard. J Chromatogr 1988; 428: 357–361.
Ette EI . Stability and performance of a population pharmacokinetic model. J Clin Pharmacol 1997; 37: 486–495.
Efron B . Bootstrap methods: another look at the jackknife. Ann Stat 1979; 7: 1–26.
Karlsson MO, Sheiner LB . The importance of modeling interoccasion variability in population pharmacokinetic analyses. J Pharmacokinet Biopharm 1993; 21: 735–750.
Jonsson EN, Karlsson MO . Xpose – an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Meth Prog Biomed 1999; 58: 51–64.
Hastie TJ . Generalized additive models. In: Chambers JM, Hastie TJ (eds) Statistical models in S. Pacific Grove. CA: Wadsworth & Books/Cole Advanced Books & Software, 1992, pp. 249–307.
Sandström M, Karlsson MO, Ljungman P, Hassan Z, Jonsson EN, Nilsson C et al. Population pharmacokinetic analysis resulting in a tool for dose individualization of busulphan in bone marrow transplantation recipients. Bone Marrow Transplant 2001; 28: 657–664.
Schiltmeyer B, Klingebiel T, Schwab M, Murdter TE, Ritter CA, Jenke A et al. Population pharmacokinetics of oral busulfan in children. Cancer Chemother Pharmacol 2003; 52: 209–216.
Aarons L, Balant LP, Mentré F, Morselli PL, Rowland M, Steimer JL et al. Practical experience and issues in designing and performing population pharmacokinetic/pharmacodynamic studies. Eur J Clin Pharmacol 1996; 49: 251–254.
Hoffer E, Akria L, Tabak A, Scherb I, Rowe JM, Krivoy N . A simple approximation for busulfan dose adjustment in adult patients undergoing bone marrow transplantation. Ther Drug Monit 2004; 26: 331–335.
Grochow LB . Busulfan disposition: the role of therapeutic monitoring in bone marrow transplantation induction regimens. Semin Oncol 1993; 20 (Suppl. 4): 18–25.
Andersson BS, Thall PF, Madden T, Couriel D, Wang X, Tran HT et al. Busulfan systemic exposure relative to regimen-related toxicity and acute graft-versus-host disease: defining a therapeutic window for IV BuCy2 in chronic myelogenous leukemia. Biol Blood Marrow Transplant 2002; 8: 477–485.
Hassan M, Fasth A, Gerritsen B, Haraldsson A, Syruckova Z, van den Berg H et al. Busulphan kinetics and limited sampling model in children with leukemia and inherited disorders. Bone Marrow Transplant 1996; 18: 843–850.
Slattery JT . Re: intravenous versus oral busulfan – perhaps not as different as suggested. Biol Blood Marrow Transplantation 2003; 9: 282–284.
Andersson BS, Kashyap A, Couriel D, Madden T, de Lima M, Thall PF et al. Intravenous busulfan in pretransplant chemotherapy: bioavailability and patient benefit. Biol Blood Marrow Transplantation 2003; 9: 722–724.
Acknowledgements
We are indebted to Professor Hiroyasu Ogata of Meiji Pharmaceutical University for his critical review of the manuscript. We thank Masaaki Kozaki for his excellent technical assistance.
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Takama, H., Tanaka, H., Nakashima, D. et al. Population pharmacokinetics of intravenous busulfan in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 37, 345–351 (2006). https://doi.org/10.1038/sj.bmt.1705252
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DOI: https://doi.org/10.1038/sj.bmt.1705252
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