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Pharmacokinetics

Population pharmacokinetic analysis resulting in a tool for dose individualization of busulphan in bone marrow transplantation recipients

Bone Marrow Transplantation volume 28, pages 657–664 (2001)Cite this article

Abstract

The aims of the present study were (1) to investigate and quantify the pharmacokinetics, including inter-occasion variability and covariate relationships, of busulphan in BMT patients and (2) to develop a user-friendly initial dosing and therapeutic drug monitoring (TDM) strategy for the treatment of those patients with busulphan. The pharmacokinetics of busulphan was studied in 64 adults and 12 children who received busulphan (1 mg/kg) four times daily for 4 days. A one-compartment model with first order absorption and a lag time was sufficient in describing the concentration-time profile. Oral clearance (CL/F) was found to be correlated to weight (+1.2%/kg), ALT (−13%/μcat/l) and concomitant phenytoin treatment (+21%). CL/F and the volume of distribution (V/F) were estimated to 9.23 l/h and 39.3 l, respectively, in a typical individual. Inter-occasion variability (9.4%) in CL/F was estimated to be less than inter-individual variability (28%), a prerequisite for the value of TDM. Bayesian CL/F estimates based on three samples were in good accordance with those based on all samples. The final population model was implemented into the program Excel. The resulting flexible and easy to use dosing program might be used for both initial and, requiring only three plasma samples, maintenance dose individualization of busulphan therapy. Bone Marrow Transplantation (2001) 28, 657–664.

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References

  1. Copelan EA, Biggs JC, Thompson JM et al. Treatment for acute myelocytic leukemia with allogeneic bone marrow transplantation following preparation with BuCy2 Blood 1991 78: 838–843

    CAS  PubMed  Google Scholar 

  2. Lu C, Braine HG, Kaizer H et al. Preliminary results of high-dose busulfan and cyclophosphamide with syngeneic or autologous bone marrow rescue Cancer Treat Rep 1984 68: 711–717

    CAS  PubMed  Google Scholar 

  3. Geller RB, Saral R, Piantadosi S et al. Allogeneic bone marrow transplantation after high-dose busulfan and cyclophosphamide in patients with acute nonlymphocytic leukemia Blood 1989 73: 2209–2218

    CAS  PubMed  Google Scholar 

  4. Santos GW, Tutschka PJ, Brookmeyer R et al. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide New Engl J Med 1983 309: 1347–1353

    Article  CAS  PubMed  Google Scholar 

  5. Slattery JT, Clift RA, Buckner CD et al. Marrow transplantation for chronic myeloid leukemia: the influence of plasma busulfan levels on the outcome of transplantation Blood 1997 89: 3055–3060

    CAS  PubMed  Google Scholar 

  6. Grochow LB, Jones RJ, Brundrett RB et al. Pharmacokinetics of busulfan: correlation with veno-occlusive disease in patients undergoing bone marrow transplantation Cancer Chemother Pharmacol 1989 25: 55–61

    Article  CAS  PubMed  Google Scholar 

  7. Slattery JT, Sanders JE, Buckner CD et al. F Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics (published erratum appears in Bone Marrow Transplant 1996 18: 829) Bone Marrow Transplant 1995 16: 31–42

    CAS  PubMed  Google Scholar 

  8. Dix SP, Wingard JR, Mullins RE et al. Association of busulfan area under the curve with veno-occlusive disease following BMT Bone Marrow Transplant 1996 17: 225–230

    CAS  PubMed  Google Scholar 

  9. Hassan M, Ehrsson H, Wallin I et al. Pharmacokinetic and metabolic studies of busulfan in rat plasma and brain Eur J Drug Metab Pharmacokinet 1988 13: 301–305

    Article  CAS  PubMed  Google Scholar 

  10. Hassan M, Fasth A, Gerritsen B et al. Busulphan kinetics and limited sampling model in children with leukemia and inherited disorders Bone Marrow Transplant 1996 18: 843–850

    CAS  PubMed  Google Scholar 

  11. Grochow LB, Krivit W, Whitley CB et al. Busulfan disposition in children Blood 1990 75: 1723–1727

    CAS  PubMed  Google Scholar 

  12. Vassal G, Deroussent A, Challine D et al. Is 600 mg/m2 the appropriate dosage of busulfan in children undergoing bone marrow transplantation? Blood 1992 79: 2475 2479

    Google Scholar 

  13. Regazzi MB, Locatelli F, Buggia I et al. Disposition of high-dose busulfan in pediatric patients undergoing bone marrow transplantation Clin Pharmacol Ther 1993 54: 45–52

    Article  CAS  PubMed  Google Scholar 

  14. Hassan M, Oberg G, Bekassy AN et al. Pharmacokinetics of high-dose busulphan in relation to age and chronopharmacology Cancer Chemother Pharmacol 1991 28: 130–134

    Article  CAS  PubMed  Google Scholar 

  15. Vassal G, Challine D, Koscielny S et al. Chronopharmacology of high-dose busulfan in children Cancer Res 1993 53: 1534–1537

    CAS  PubMed  Google Scholar 

  16. Gibbs JP, Gooley T, Corneau B et al. The impact of obesity and disease on busulfan oral clearance in adults Blood 1999 93: 4436–4440

    CAS  PubMed  Google Scholar 

  17. Gibbs JP, Murray G, Risler L et al. Age-dependent tetrahydrothiophenium ion formation in young children and adults receiving high-dose busulfan Cancer Res 1997 57: 5509–5516

    CAS  PubMed  Google Scholar 

  18. Grochow LB . Busulfan disposition: the role of therapeutic monitoring in bone marrow transplantation induction regimens Semin Oncol 1993 20: (Suppl. 4) 18–25; quiz 26

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Chattergoon DS, Saunders EF, Klein J et al. An improved limited sampling method for individualised busulphan dosing in bone marrow transplantation in children Bone Marrow Transplant 1997 20: 347–354

    Article  CAS  PubMed  Google Scholar 

  21. Schuler U, Schroer S, Kuhnle A et al. Busulfan pharmacokinetics in bone marrow transplant patients: is drug monitoring warranted? Bone Marrow Transplant 1994 14: 759–765

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  23. Hassan M, Ehrsson H, Smedmyr B et al. Cerebrospinal fluid and plasma concentrations of busulfan during high-dose therapy Bone Marrow Transplant 1989 4: 113–114

    CAS  PubMed  Google Scholar 

  24. Yeager AM, Wagner JE Jr, Graham ML et al. Optimization of busulfan dosage in children undergoing bone marrow transplantation: a pharmacokinetic study of dose escalation Blood 1992 80: 2425–2428

    CAS  PubMed  Google Scholar 

  25. Vassal G, Gouyette A, Hartmann O et al. Pharmacokinetics of high-dose busulfan in children Cancer Chemother Pharmacol 1989 24: 386–390

    Article  CAS  PubMed  Google Scholar 

  26. Hassan M, Ehrsson H . Determination of busulfan in human plasma by gas chromatography with electron-capture detection (letter) J Chromatogr 1988 434: 330

    Article  CAS  PubMed  Google Scholar 

  27. Beal S, Sheiner L . NONMEM Users Guide. Group NP (ed) San Fransicso: University of California 1999

    Google Scholar 

  28. Karlsson MO, Sheiner LB . The importance of modeling interoccasion variability in population pharmacokinetic analyses J Pharmacokinet Biopharm 1993 21: 735–750

    Article  CAS  PubMed  Google Scholar 

  29. 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

    Article  CAS  Google Scholar 

  30. Hassan M, Oberg G, Ehrsson H et al. Pharmacokinetic and metabolic studies of high-dose busulphan in adults Eur J Clin Pharmacol 1989 36: 525–530

    Article  CAS  PubMed  Google Scholar 

  31. Vassal G, Fischer A, Challine D et al. Busulfan disposition below the age of three: alteration in children with lysosomal storage disease Blood 1993 82: 1030–1034

    CAS  PubMed  Google Scholar 

  32. Hassan M, Ljungman P, Bolme P et al. Busulfan bioavailability Blood 1994 84: 2144–2150

    CAS  PubMed  Google Scholar 

  33. Hassan M, Oberg G, Bjorkholm M et al. Influence of prophylactic anticonvulsant therapy on high-dose busulphan kinetics Cancer Chemother Pharmacol 1993 33): 181–186

    Article  Google Scholar 

  34. Sheiner LB, Beal SL . Bayesian individualization of pharmacokinetics: simple implementation and comparison with non-Bayesian methods J Pharmaceut Sci 1982 71: 1344–1348

    Article  CAS  Google Scholar 

  35. Pawlowska AB, Blazar BR, Angelucci E et al. Relationship of plasma pharmacokinetics of high-dose oral busulfan to the outcome of allogeneic bone marrow transplantation in children with thalassemia Bone Marrow Transplant 1997 20: 915–920

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by the Swedish Children Cancer Society (grant 1999/033) and Swedish Cancer Society (grants 4147-B99–02XBB and 3340-B97–06XAA).

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Authors and Affiliations

  1. Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy, Faculty of Pharmacy, Uppsala University, Sweden

    M Sandström, MO Karlsson & EN Jonsson

  2. Department of Medicine, Division of Hematology, Huddinge University Hospital, Stockholm, Sweden

    P Ljungman

  3. Department of Medicine, Division of Hematology, Laboratory of Hematology, KFC Novum, Huddinge University Hospital, Stockholm, Sweden

    Z Hassan, C Nilsson & M Hassan

  4. Division of Clinical Immunology, Center for Allogeneic Stem Cell Transplantation, Huddinge University Hospital, Stockholm, Sweden

    O Ringden

  5. Department of Medicine, Division of Hematology, Uppsala University Hospital, Uppsala, Sweden

    G Öberg

  6. Department of Pediatrics, Lund University Hospital, Lund, Sweden

    A Bekassy

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Sandström, M., Karlsson, M., Ljungman, P. et al. Population pharmacokinetic analysis resulting in a tool for dose individualization of busulphan in bone marrow transplantation recipients. Bone Marrow Transplant 28, 657–664 (2001). https://doi.org/10.1038/sj.bmt.1703229

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